A Study of Intravenous Zanamivir Versus Oral Oseltamivir in Adults and Adolescents Hospitalized With Influenza

Phase 3

Completed

Conditions: Influenza, Human

Interventions: Drug: Zanamivir
Drug: Placebo to match zanamivir
Drug: Placebo to match oseltamivir
Drug: Oseltamivir

Registration Number: NCT01231620

Lead Sponsor: GlaxoSmithKline

Brief Summary: The purpose of this study is to test the safety and efficacy of zanamivir given intravenously and how well it works at two different doses in hospitalized adolescents and adults with flu. Zanamivir will be compared with oseltamivir, which is used for treating flu.

Detailed Description: The recent influenza pandemic has highlighted the need for alternative formulations for anti-influenza therapies. This will be an international Phase III, double-blind, double-dummy, 3-arm study to evaluate the efficacy, antiviral activity and safety of IV zanamivir 600 mg twice daily compared to oral oseltamivir 75 mg twice daily, and 600 mg IV zanamivir twice daily compared to 300 mg IV zanamivir for 5 days in hospitalized subjects with laboratory confirmed or suspected influenza infection. For a given subject, the initial 5-day treatment course may be extended for up to 5 additional days if clinical symptoms or patient characteristics as assessed by the investigator warrant further treatment. Alternatively, if the investigator considers that a subject is failing to improve clinically on their randomized treatment, the investigator can choose to initiate the switch/rescue option (600 mg IV zanamivir twice daily) on any day from Day 6 through Day 10 for up to an additional 5 days of treatment. On switching treatments, subjects complete a maximum of 14 days of treatment and are followed-up to Post-Treatment +28 Days.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 626

Inclusion Criteria

Male or female aged 16 years; a female is eligible to enter and participate in the study if she is:
1. of non-childbearing potential (i.e., physiologically incapable of becoming pregnant, including any female who is post- menopausal); or,
2. of child-bearing potential, has a negative pregnancy test at Baseline, and agrees to use protocol specified methods of birth control while on study.
Vital signs criteria defined as 3 or more of the following at Baseline:
1. Presence of fever [oral temperature of 38°C or equivalent] at Baseline. However, this requirement is waived if the subject has a history of fever within in the 24 hours prior to Baseline; or, if the subject reported symptoms of feverishness at some time during the 48 hours prior to Baseline.
  
  AND at least 2 out of the following 4:
2. Oxygen saturation <95% on room air by trans-cutaneous method or need for any supplemental oxygenation or ventilatory support, or increase in oxygen supplementation requirement of ≥2 litres for subjects with chronic oxygen dependency. For those subjects with a history of chronic hypoxia (without supplemental oxygen), an oxygen saturation of at least 3% below the patient's historical baseline oxygen saturation will satisfy this criterion.
3. Respiration rate >24 breaths per minute. For those subjects who require ventilatory support or oxygen supplementation, this requirement is waived.
4. Heart rate >100 beats per minute.
5. Systolic blood pressure <90 mmHg.
Onset of influenza symptoms within 6 days prior to study enrolment. Symptoms may include cough, dyspnea, sore throat, feverishness, myalgias, headache, nasal symptoms (rhinorrhea, congestion), fatigue, diarrhea, anorexia, nausea and vomiting.
Clinical symptoms of influenza with positive influenza diagnostic test result or strong suspicion of influenza illness based on clinical symptoms and local surveillance information.
Subjects willing and able to give written informed consent to participate in the study and to adhere to the procedures stated in the protocol, or legally acceptable representative willing and able to give written informed consent on behalf of the subject for minors, unconscious adults and those incapable of consenting themselves due to their medical condition, or included as permitted by local regulatory authorities, IRB/IECs or local laws.
Severity of any medical illness that, in the Investigator's judgement, justifies hospitalization of the subject for treatment and supportive care
French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category

Exclusion Criteria

Subjects who have taken more than a total of 3 days (6 doses) of approved anti-influenza therapy in the period from onset of symptoms and prior to enrolment.
Subjects who, in the opinion of the investigator, are not likely to survive beyond 48 hours from Baseline.
Subjects who are considered to require concurrent therapy with another influenza antiviral medication.
Subjects who are known or suspected to be hypersensitive to any component of the study medications.
Subjects with creatinine clearance ≤10 mL/min who are not being treated with continuous renal replacement therapy (CRRT).
Subjects who require Extra Corporeal Membrane Oxygenation (ECMO) at Baseline
Subjects who require routine/intermittent hemodialysis or continuous peritoneal dialysis (due to inability to provide appropriate dosing schedule for oseltamivir) at Baseline. CRRT modalities are allowed.
Liver toxicity criteria based on local laboratory results obtained within 24 hours of Baseline:
1. ALT or AST 3xULN and bilirubin 2xULN
2. ALT 5xULN
Underlying chronic liver disease with evidence of severe liver impairment.
History of severe cardiac disease or clinically significant arrhythmia (either on ECG or by history) which, in the opinion of the Investigator, will interfere with the safety of the individual subject.
Females who are pregnant or are breastfeeding.
Treatment with investigational parenteral anti-influenza drugs (IV peramivir, IV zanamivir or IV oseltamivir) in the 4 weeks prior to Baseline.
French and Korean subjects: the French or Korean subject has participated in any study using an investigational drug during the previous 30 days.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Intravenous (IV) Zanamivir 300mg Twice Daily	Zanamivir	300mg of IV zanamivir infusion twice daily plus oral oseltamivir placebo twice daily
Intravenous (IV) Zanamivir 300mg Twice Daily	Placebo to match oseltamivir	300mg of IV zanamivir infusion twice daily plus oral oseltamivir placebo twice daily
Intravenous (IV) Zanamivir 600mg Twice Daily	Zanamivir	600mg of IV zanamivir infusion twice daily plus oral oseltamivir placebo twice daily
Intravenous (IV) Zanamivir 600mg Twice Daily	Placebo to match oseltamivir	600mg of IV zanamivir infusion twice daily plus oral oseltamivir placebo twice daily
Oral Oseltamivir 75mg Twice Daily	Placebo to match zanamivir	75mg oral oseltamivir twice daily plus intravenous placebo zanamivir twice daily
Oral Oseltamivir 75mg Twice Daily	Oseltamivir	75mg oral oseltamivir twice daily plus intravenous placebo zanamivir twice daily

Primary Outcome Measures

Name	Time	Method
Time to Clinical Response (TTCR) in Participants With Confirmed Influenza	Up to 42 days	Clinical response is defined as the resolution of at least 4 of the 5 vital signs (temperature, oxygen saturation, respiratory status, heart rate, systolic blood pressure) within the respective resolution criteria, maintained for at least 24 hours, or hospital discharge, whichever occurred first. This analysis was performed for Influenza positive population, for those with symptom onset less than or equal to (\<=) 4 days, and for those on mechanical (mech) ventilation or in intensive care unit (ICU). 99 days is censored time for the participants who did not achieve TTCR.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants With Respiratory Improvement	Up to 42 days	Respiratory Status (RS) is a component of TTCR. Response criteria included the return to the pre-morbid oxygen requirement (participants with chronic oxygen use), a need for supplemental oxygen (administered by any modality: ventilator, non-invasive ventilation, facemask, facetent, nasal canula, etc.) to no need for supplemental oxygen, or a respiratory rate of =\<24 breaths/minute (without supplemental oxygen). Data are presented as the percentage of participants achieving respiratory improvement.
Number of Participants With All Cause and Attributable Mortality at Day 14, at Day 28, and at the End of Study Visit	On or before Day 14, Day 28, End of Study Visit (assessed up to 42 days)	The number of participants who died on or before Day 14, Day 28, and the End of Study Visit were summarized.
Change From Baseline in the Katz Activities of Daily Living (ADL) Score and Each ADL Activity Score	Baseline (Day 1) and up to 42 days	The Katz ADL scores were collected for bathing, dressing, toileting, transferring, continence, and feeding activities and were assessed once daily during the treatment period/hospitalization and once at each post-treatment Clinic Visit. For the six individual activities, a score of 1 indicates independence, and a score of 0 indicates dependence. The total score is generated by adding the scores of all six activities. A total score of 6 indicates that the participant was independent; a total score of 0 indicates that the participant was very dependent. Baseline is defined as the pre-dose value collected on Study Day 1. Change from Baseline is defined as the difference at each time point (Day 5/6, and Day 10/11, and last day S/R if treatment was extended beyond 5 days) and the end of the study (post-treatment \[PT\] +28 Days) compared to Baseline.
Median Time to Return to Pre-morbid Functional Status as Measured by the Katz ADL Score and Each ADL Activity Score	Up to 42 days	Pre-morbid functional status is defined as the best functional status in the 4 weeks prior to enrolment. Median time to return to pre-morbid functional status was assessed via the Katz ADL score (bathing, dressing, toileting, transferring, continence, and feeding activities). For the six individual activities, a score of 1 indicates independence, and a score of 0 indicates dependence. The total score is generated by adding the scores of all six activities. A total score of 6 indicates that the participant was independent; a total score of 0 indicates that the participant was very dependent.
Number of Participants Who Returned to Their Pre-morbid Functional Status as Assessed Per the Katz ADL Score and Each ADL Activity Score at the End of the Study	Up to 42 days	Pre-morbid functional status is defined as the best functional status in the 4 weeks prior to enrolment. The number of participants who returned to their pre-morbid functional status at the end of the study assessed per the Katz ADL score (bathing, dressing, toileting, transferring, continence and feeding activities) is summarized.
Median Time to Return to the Pre-morbid Level of Activity as Measured by the 3-point Scale	Up to 42 days	Median time to return to pre-morbid level of activity was assessed once daily during treatment/hospitalization and once at each post-treatment assessment and was measured using the 3- point scale (bed rest, limited ambulation, or unrestricted).
Number of Participants With the Indicated Clinical Symptoms of Influenza	Up to 42 days	Influenza clinical symptoms included nasal symptoms (rhinorrhea, congestion), feverishness, cough, myalgias, fatigue, diarrhea, anorexia, dyspnea, headache, sore throat, nausea, and vomiting. Influenza symptoms were assessed once daily during inpatient hospitalization and once at each post-treatment assessment.
Median Time of Duration of Clinical Symptoms of Influenza	Up to 42 days	Influenza clinical symptoms included nasal symptoms (rhinorrhea, congestion), feverishness, cough, myalgias, fatigue, diarrhea, anorexia, dyspnea, headache, sore throat, nausea, and vomiting. Influenza symptoms were assessed once daily during inpatient/hospitalization and once at each post-treatment assessment.
Number of Participants With Complications of Influenza and Associated Antibiotic Use	Up to 42 days	The number of participants with complications of influenza and associated antibiotic use were summarized
Number of Participants With the Indicated Ventilation Status: Modality of Invasive and Non-invasive Ventilator Support and Oxygen Supplementation	Up to 42 days	Ventilation status was assessed three times daily during the treatment period/hospitalization. Ventilation status was assessed once daily during inpatient/hospitization and once at each post-treatment clinic visit. The number of participants reported for machine-assisted: extracorporeal membrane oxygenation (ECMO), endotracheal mechanical ventilation, and supplemental oxygen delivery (SOD), no supplemental oxygen (O2) or ventilation support, Respiratory support at "any time (AT) on study" and at Baseline (Day 1) are summarized. Data for the "any time (AT) on study" time point was reported.
Median Time of Duration of Invasive and Non-invasive Ventilator Support and Oxygen Supplementation	Baseline (Day 1) and up to 42 days	Ventilation status was assessed three times daily during the treatment period/hospitalization. Ventilation status was assessed once daily during inpatient/hospitalization and once at each post-treatment clinic visit.
Median Time of Duration of Hospitalization and Intensive Care Unit (ICU) Stay	Day 1 to the end of the study (assessed up to 42 days)	Hospital duration and ICU duration was assessed from the first day of dosing. Hospital duration was calculated as the discharge date minus the admission date + 1. Hospital duration while on study was the earlier of discharge, completion, or withdrawal minus the later of the admission date or the study start date + 1. ICU duration-Modified was calculated as the original ICU duration minus ICU days prior to Study Day 1.
Median Time to the Absence of Fever and Improved Respiratory Status, Oxygen Saturation, Heart Rate, and Systolic Blood Pressure	Baseline (Day 1) and up to 42 days	The absence of fever is defined as a non-axillary temperature recording \<=36.6 degrees Celsius axillary, \<= 37.2 degrees Celsius oral or \<= 37.7 degrees Celsius core. Respiratory Status (RS) response criteria included the return to the pre-morbid oxygen requirement (participants with chronic oxygen use), or the need for supplemental oxygen (administered by any modality: ventilator, non-invasive ventilation, facemask, facetent, nasal canula, etc.) to no need for supplemental oxygen, or a respiratory rate =\<24 breaths/minute (without supplemental oxygen). Oxygen saturation response criteria: \>=95% (without supplemental oxygen). Heart rate response criteria: =\<100 beats/minute. Systolic blood pressure response criteria: \>=90 millimeters of mercury. Vital signs were assessed three times daily during the treatment period/hospitalization. Vital signs were assessed once daily during inpatient/hospitization and once at each post-treatment clinic visit.
Median Time to Virologic Improvement	Baseline (Day 1) and up to 42 days	Virologic improvement is defined as a 2 log drop in viral load or sustained undetectable viral ribonucleic acid (RNA) (on two successive occasions) as measured by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) from nasopharyngeal samples. Nasopharyngeal swabs were collected daily from Baseline through Day 5. If randomized treatment was continued beyond Day 5, samples were taken on Treatment Days 6, 8, 10 and on the last day of randomized treatment. For participants who utilized the Switch (S)/Rescue (R) option, samples were taken on S/R Day 1, S/R Day 3, S/R Day 5, or S/R Day 6, whichever was the last day of S/R treatment. Nasopharyngeal swabs were taken if the participant was symptomatic and continued to be hospitalized on the Post-Treatment +2, +5, +9, +16, and +28 day assessment.
Change From Baseline in Quantitative Virus Culture From Nasopharyngeal Swabs Positive at Baseline	Baseline (Day 1), Day 3, Day 5, Day 8, Day 10, Day 11 and/or last day of randomized treatment, if randomized treatment was extended beyond 5 days, and S/R Day 5/6 (up to Day 14) if applicable	Nasopharyngeal swabs were collected daily from Baseline through Day 5. If randomized treatment was continued beyond Day 5, samples were taken on Treatment Day 6, Day 8, Day 10, Day 11, and the last day of randomized treatment. For participants who utilized the S/R option, samples were taken on S/R Day1, S/R Day3, S/R Day5, or S/R Day6, whichever was the last day of S/R treatment. Samples were taken if the participant was symptomatic and continued to be hospitalized on the Post-Treatment +2, +5, +9, +16 and +28Day assessment. Viral load was measured by Quantitative Virus Culture, log10 50% Tissue Culture Infectious Dose (TCID50)/milliliter (mL). Baseline is defined as the pre-dose value collected on Study Day 1. Change from Baseline was calculated as the post-Baseline value minus Baseline value .
Change From Baseline Viral Load (Influenza A or B) by qPCR From Nasopharyngeal Swabs Positive at Baseline	Baseline (Day 1), Day 3, Day 5, Day 8, Day 10, Day 11 and/or last day of randomized treatment, if randomized treatment was extended beyond 5 days, and S/R Day 5/6 (up to Day 14) if applicable	Nasopharyngeal swabs were collected daily from Baseline through Day 5. If randomized treatment was continued beyond Day 5, samples were taken on Treatment Day 6, Day 8, Day 10, Day 11, and the last day of randomized treatment. For participants who utilized the S/R option, samples were taken on S/R Day 1, S/R Day 3, S/R Day 5, or S/R Day 6, whichever was the last day of S/R treatment. Samples were taken if the participant was symptomatic and continued to be hospitalized on the post-treatment +2, +5, +9, +16 and +28 day assessment. Viral load as measured by PCR. Baseline is defined as the pre-dose value collected on Study Day 1. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
Number of Participants With no Detectable Viral RNA and the Absence of Cultivable Virus in Lower Respiratory Samples (Bronchoalveolar Lavage Sample [BAL], Endotracheal Aspirate)	Baseline (Day 1) and up to 42 days	Lower respiratory samples included BAL and endotracheal aspirates. Endotracheal aspirates were requested in participants (par.) who were intubated. Upper (nasopharyngeal swabs) and lower (Endotracheal aspirates, bronchoalveolar lavage samples) respiratory samples were collected daily from Baseline/Day 1 through Day 5 and Day 6 (if the last day of randomized treatment \[trt\]). Endotracheal aspirates were collected in participants who were intubated. If trt was continued beyond Day 5, additional samples were taken on Trt Day 6, Day 8, Day 10, and/or the day of the last dose of randomized trt, if applicable, and S/R Day 1, S/R Day 3, S/R Day 5, or S/R Day 6 if the last day of S/R trt. If the par. was symptomatic and hospitalized, samples were taken on the Post-Trt +2, +5, +9, +16 assessment days, and at the Post-Trt \[PT\]+28 Day assessment. Assessment of samples was done by quantitative RT-PCR and viral culture.
Median Time to no Detectable Viral RNA and the Absence of Cultivable Virus in Any Obtained Sample (Upper and Lower Respiratory Samples)	Baseline (Day 1) and up to 42 days	Upper (nasopharyngeal swabs) and lower (Endotracheal aspirates, bronchoalveolar lavage samples, where available) respiratory samples were collected daily from Baseline/Day 1 through Day 5 and Day 6 (if the last day of randomized treatment). Endotracheal aspirates were collected in participants who were intubated. If treatment was continued beyond Day 5, additional samples were taken on Treatment Day 6, Day 8, Day 10, and/or the day of the last dose of randomized treatment, if applicable, and S/R Day 1, S/R Day 3, S/R Day 5, or S/R Day 6 if the last day of S/R treatment. If the participant was symptomatic and hospitalized, samples were taken on the Post-treatment+2, +5, +9, +16 assessment days, and at the Post-Treatment +28 Day. Assessment of samples was done by quantitative RT-PCR.
Number of Participants With Resistance-associated Mutations Detected in the Neuraminidase (NA) and Hemagglutinin (HA) Gene of Influenza A and B Viruses in Nasopharyngeal Swabs and Endotracheal/BAL Samples	Baseline (Day 1) and up to 42 days	Nasopharyngeal swabs and endotracheal /BAL samples were collected for viral susceptibility analysis. Susceptibility analyses consisted of phenotyping and genotyping. Resistance mutations were detected by genotyping. Viral susceptibility to zanamivir and oral oseltamivir at Baseline and throughout treatment determined by NA and HA (gene of influenza A and B viruses) sequence analysis and NA enzyme inhibition. Number of participants with viral mutation events are summarized, this includes all resistance mutations (substitutions) i.e. those present at Baseline and those that emerged during treatment.
Number of Participants With Any Adverse Event (AE) Considered to be Related to Study Treatment	Up to 42 days	An AE is defined as any untoward medical occurrence in a participant temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse, or misuse. All AEs were assessed by the Investigator as related or not related to the study treatment.
Number of Participants With Any Severe or Grade 3/4 AE	Up to 42 days	An AE is defined as any untoward medical occurrence in a participant temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse, or misuse. AEs that occurred during the study were evaluated by the Investigator and graded according to the Division of Acquired Immunodeficiency Syndrome (DAIDS) table for grading the severity of AEs. Grade 3=severe; Grade 4=potentially life threatening.
Number of Participants Who Permanently Discontinued the Study Treatment Due to an AE	Up to 42 days	An AE is defined as any untoward medical occurrence in a participant temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse, or misuse.
Number of Participants Who Were Permanently Discontinued From the Study Due to an AE	Up to 42 days	An AE is defined as any untoward medical occurrence in a participant temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse, or misuse.
Serum Concentration of IV Zanamivir	Day 1 and Day 4	Pharmacokinetic samples were collected at four time points to characterize peak concentration (end of infusion; C\[EOI\]) after the first dose on Day 1 and on Day 4 to characterize the pre-dose concentration (C\[0\]), the peak concentration C(EOI), and the trough concentration at 11-12 hours post-dose (C\[12\]) of zanamavir. Data was summarized by Creatinine clearance (CL) Category. The dose on Day 1 is the initial dose (unadjusted) and the dose on Day 4 is the maintenance dose.
Number of Participants With Any Severe or Grade 3/4 Treatment-related AE	Up to 42 days	An AE is defined as any untoward medical occurrence in a participant temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse, or misuse. AEs that occurred during the study were evaluated by the Investigator and graded according to the DAIDS table for grading the severity of adult and pediatric AEs. Grade 3=severe; Grade 4=potentially life threatening. All AEs were assessed by the Investigator as related or not related to the study treatment.
Number of Participants With the Indicated Chemistry Laboratory Values Shifts From Baseline (Day 1) and up to 42 Days	Baseline (Day 1) and up to 42 days	Samples for laboratory assessments were collected at Baseline (Day 1), Day 3, Day 5/6, Day 8, Day 10/11 (or last day of randomized treatment), switch/rescue (S/R) Day 1, S/R Day 3, and S/R Day 5/6 (last day of S/R treatment for those participants who utilized this option), Post-Treatment +2 (if hospitalized), and Post-Treatment +5, +16, and +28 Days. Clinical chemistry parameters included albumin, alkaline phosphatase (ALP), alanine amino transferase (ALT), aspartate amino tranferase (AST), total bilirubin, calcium, creatine kinase, chloride, carbon dioxide content (CO2), creatinine, potassium, magnesium, sodium. Per the DAIDS table for grading the severity of adult and pediatric AEs, Grade (G) 1=mild, G2= moderate, G3=severe and G4=potentially life threatening. The number of participants with values that were G1, G2, G3 and G4 relative to the normal range are summarized.
Number of Participants With the Indicated Hematology Values Shifts From Baseline (Day 1) and up to 42 Days	Baseline (Day 1) and up to 42 days	Blood samples for laboratory assessments were collected at Baseline (Day 1), Day 3, Day 5/6, Day 8, Day 10/11 (or last day of randomized treatment), S/R Day 1, S/R Day 3, and S/R Day 5/6 (last day of S/R treatment for those participants who utilized this option), Post-Treatment +2 (if hospitalized), and Post-Treatment +5, +16, and +28 Days. Hematology parameters included hemoglobin, lymphocytes, total neutrophils, platelet count, and white blood cell (WBC) count. Per the DAIDS table for grading the severity of adult and pediatric AEs, Grade (G) 1=mild, G2= moderate, G3=severe and G4=potentially life threatening. The number of participants with values that were G1, G2, G3 and G4 relative to the normal range for the indicated hematology parameters is summarized. Baseline is defined as the pre-dose value collected on Study Day 1.
Number of Participants With the Indicated Treatment-emergent (TE) Grade (G) 3/4 Clinical Chemistry Toxicities	Baseline (Day 1) and up to 42 days	A toxicity was considered to be TE if it was greater than the Baseline grade, and if it had developed or increased post-Baseline in intensity (and prior to the last dose of investigational product). Clinical chemistry parameters included albumin, ALP, ALT, AST, total bilirubin, calcium, creatine kinase, chloride, CO2/bicarbonate, creatinine, potassium, magnesium and sodium. Per the DAIDS table for grading the severity of adult and pediatric AEs, Grade 3=severe and Grade 4=potentially life threatening. Baseline is defined as the pre-dose value collected on Study Day 1.
Number of Participants With the Indicated Treatment-emergent (TE) Grade 3/4 Hematology Toxicities	Baseline (Day 1) and up to 42 days	A toxicity was considered to be TE if it was greater than the Baseline grade, and if it had developed or increased post-Baseline in intensity (and prior to the last dose of investigational product). The hematology parameters included hemoglobin, lymphocytes, total neutrophils, platelet count, and WBC count. Per the DAIDS table for grading the severity of adult and pediatric AEs, Grade 3=severe and Grade 4=potentially life threatening. Baseline is defined as the pre-dose value collected on Study Day 1.
Median Quantity of Oxygen Delivery Measured at Baseline (Day 1) and During the Study	Baseline (Day 1) and during the study	Oxygen delivery were assessed three times daily at Baseline (Day 1) and during the treatment period/hospitalization (ideally at least 6 hours apart) and once daily during inpatient/hospitalization and once at Post +5 days, +16 days, and +28 days clinic visits. The median quantity of oxygen delivery during the study was not summarized since the data was not collected in a way to accurately calculate values. Baseline is defined as the pre-dose value collected on Study Day 1.
Number of Participants Assessed as Normal/Abnormal (Clinically Significant [CS] and Not Clinically Significant [NCS]) for 12-lead Electrocardiogram (ECG) at Baseline (Day 1) and Day 4	Baseline (Day 1) and Day 4	On Baseline/Day 1, a 12-lead ECG was obtained within approximately 24 hours prior to dosing. The number of participants with an ECG status of normal and abnormal CS or NCS, as determined by the Investigator, is reported. Normal=all ECG parameters within the accepted normal ranges. Abnormal=ECG findings outside of normal ranges. CS=ECG with a CS abnormality that meets exclusion criteria. NCS=ECG with an abnormality that is not CS nor meets exclusion criteria, per Investigator, based on reasonable standards of clinical judgment. In the original protocol ECGs were also done on Day 4, however, amendment 2 removed this requirement and therefore not all participants had Day 4 ECGs.