Influenza
Conditions
Keywords
influenza, oseltamivir, Tamiflu®, antiviral, children, infants
Brief summary
The purpose of this study is to learn how to treat influenza in children less than 2 years of age. Tamiflu®, the drug being studied, is approved for treatment of children 1 year of age and older with influenza. Researchers want to learn more about the activity of Tamiflu® in the body to determine a dose of that is safe, well-tolerated, and effective in young children with influenza. Children less than 24 months of age with confirmed influenza will receive Tamiflu® 2 times a day for 5 days. Older participants will be enrolled first and younger children will be enrolled after the safety data is reviewed for older participants. Study procedures include blood samples, swabs from inside the nose, and body and nervous system evaluations. Participants may be involved in study related procedures for up to 37 days.
Detailed description
Oseltamivir is approved for prophylaxis and treatment of children 1 year of age and older with influenza. Influenza treatments for children under the age of 1 year are needed because mortality from influenza is high among this age group, even when there are no underlying medical conditions. Oseltamivir is frequently used off-label in children less than 1 year of age, with no data supporting the doses being used. Given the risk of severe or fatal influenza infection in infants, the lack of repeat dose pharmacokinetic (PK) data in children less than 2, the need for treatments in this population of children, and the fact that oseltamivir is being used off-label in this population, the current study will systematically study the PK and safety of oseltamivir in children less than 2 years of age with confirmed influenza to determine the appropriate dose to be used in these age groups. This data will be critical to pediatricians caring for these potentially gravely ill infants. This study is a prospective, age-stratified PK/pharmacodynamic (PD) and safety evaluation of oseltamivir therapy in children less than 24 months of age with confirmed influenza infection. Participants will be stratified by age into the following enrollment scheme at study initiation: 12-23 months (Cohort I), 9-11 months (Cohort II), 6-8 months (Cohort III), 3-5 months (Cohort IV) and 0-2 months (Cohort V). At study onset, Cohort II and III will be enrolled simultaneously. Cohorts IV and V will be enrolled sequentially by decreasing age groups predicated upon the PK and safety data from the preceding cohort. In the event of a public health emergency, the Data Safety Monitoring Board (DSMB) or Food and Drug Administration (FDA) may authorize the following modifications to the proposed enrollment plan: the opening of younger age cohorts without the full dataset from the next higher age cohort, the re-opening of previously closed cohorts to obtain additional data and/or the over-enrollment of any of the 5 cohorts. The oldest cohort (Cohort I) may be enrolled at any time during the study. The primary study objective is to define the PK of oseltamivir and oseltamivir carboxylate in children with confirmed influenza less than 2 years of age. The oseltamivir dose initially evaluated in Cohort I was the approved dose of 30 mg twice a day (bid). However, the oseltamivir carboxylate area under the curve (AUC)12 values for 5 of the 9 subjects enrolled in Cohort I as of August 5, 2009, were below the lower range utilized for the other cohorts in the study, as was the GM AUC12 for Cohort I as a group \[(2589 nanograms per hour per milliliter (ngxh/mL)\]. As a consequence, the DSMB recommended on August 5, 2009, that the protocol be amended to utilize weight-based dosing of oseltamivir in subjects subsequently enrolled in Cohort I, and to employ the targeted AUC approach used for Cohorts II-V for this cohort as well. Based upon the PK data available as of that date, the initial weight-based dose to be evaluated for Cohort I is 3.5 mg/kg bid. A dose of oseltamivir 3 mg/kg/dose orally bid for 5 days (10 doses) will be administered to the first 9 subjects in each of Cohorts II-III. Additional subjects may be enrolled if the target AUC12 range is not achieved. The proposed dose for subjects enrolled in Cohorts IV and V will be 3 mg/kg/dose orally bid for 5 days (10 doses), although this dose may be adjusted prior to opening Cohort IV or V based on the dose required to achieve the target oseltamivir carboxylate AUC12 range in the previous cohort.
Interventions
DRUGoseltamivir (Tamiflu®)
Oseltamivir is supplied as a white powder blend for constitution to a suspension. It is supplied in 100 ml amber glass bottles with 30 grams of powder for oral suspension, a plastic adapter, a plastic oral dispenser and a plastic measuring cup. Initially subjects in Cohort I received oseltamivir 30 mg orally twice daily for 5 days. The DSMB recommended on 05-Aug-2009 that weight based dosing of oseltamivir for subjects subsequently enrolled in Cohort I. Based on pharmacokinetic data available as of that date, the initial weight-based dose to be evaluated for Cohort I is 3.5 mg/kg twice a day. Cohort II and Cohort III will receive oseltamivir at 3.0 mg/kg/dose orally twice daily for 5 days. Cohorts IV and V will receive 3.0 mg/kg/dose orally twice daily for 5 days, this dose may be adjusted.
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 23 Months
Healthy volunteers
No
Inclusion criteria
* Signed informed consent from parent(s) or legal guardian(s). * Age: Cohort I: 12 - 23 mo. Cohort II: 9 - 11 mo. Cohort III: 6 - 8 mo. Cohort IV: 3 - 5 mo. Cohort V: 0 - 2 mo. * Confirmed laboratory diagnosis of influenza by viral culture or rapid influenza diagnostic test within 96 hours prior to study enrollment. * Duration of influenza symptoms less than or equal to 96 hours.
Exclusion criteria
* Concomitant vomiting illness that would preclude ability to take drug. * Immunocompromised subject (e.g., malignancy, congenital agammaglobulinemia, HIV). * Documented renal impairment (e.g., polycystic renal disease, nephrectomy, renal transplantation, renal agenesis, dialysis requirement, renal failure, nephrotic syndrome at any time prior to enrollment, current receipt of diuretic therapy). * Documented hepatic impairment (e.g., congenital hepatitis, biliary atresia, cholelithiasis). * Gastrointestinal abnormality which might hinder absorption of an oral medication. * Current receipt of inotropic drugs (e.g., epinephrine, norepinephrine, dopamine, dobutamine). * History of seizures. * Documented congenital malformations of the central nervous system defined at birth (e.g., hydranencephaly, prosencephaly, spina bifida).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Oseltamivir Carboxylate AUC12 (Area Under the Curve). | Day 3 of drug administration | The oseltamivir carboxylate AUC12 was derived from a series of five blood draws over 10 to 12 hours. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number and Characteristics of Adverse Events (AEs) Described as Neurological Events. | Duration of study, from receipt of the first dose of study drug and continuing through study visit Day 30 plus or minus 3 days. | Any neurological event that occurred post first dose of drug administration that was not present at baseline was considered an AE. Expected flu symptoms were not reported as AEs but were collected separately. |
| Incidence of Treatment Emergent AEs and Drug Related AEs by Cohort and Toxicity Grade | Duration of study, from receipt of the first dose of study drug and continuing through study visit Day 30 plus or minus 3 days | Any event considered to be related to the study drug that occurred post first dose of drug administration that was not present at baseline was considered an AE. Expected flu symptoms were not reported as AEs but were collected separately. The Division of AIDS Toxicity Tables (DIAIDS) were used to grade the events. |
| Incidence of Treatment Emergent AEs and Drug Related AEs by Cohort Leading to Discontinuation of Study Medication | Duration of study, from receipt of the first dose of study drug and continuing through study visit Day 5 plus or minus 1 day | Study drug was administered for 5 days; any event that occurred prior to the last dose of study medication that was considered related to an AE and that caused the subject to stop taking study drug. |
| Overall Reported Adverse Events (AEs) Thought to be Associated With Study Therapy. | Duration of study, from receipt of the first dose of study drug and continuing through study visit Day 30 plus or minus 3 days. | Any event considered associated with drug that occurred post first dose of drug administration that was not present at baseline was considered an AE. Expected flu symptoms were not reported as AEs but were collected separately. |
| Correlation of Clearance of Viral RNA by Culture With Pharmacokinetic Parameters by Cohort | Day to negative viral load for subjects positive at baseline | The Spearman coefficient and the p-values were computed between the clearance of Viral RNA and Oseltamivir Carboxylate Area under the curve from 0 to 12 hours (AUC0-12) |
| Correlation of Clearance of Viral RNA by Polymerase Chain Reaction (PCR) to Pharmacokinetic Parameters by Cohort. | From date of enrollment until the date of first documented absence of viral load by culture, assessed up to 10 days after enrollment. | The Spearman coefficient and the p-values were computed between the clearance of viral RNA and oseltamivir carboxylate Area Under the Curve from 0 to 12 hours (AUC 0-12) |
| Incidence of All Serious Adverse Events by Cohort and System Organ Class (SOC) | Duration of study, from receipt of the first dose of study drug and continuing through study visit Day 30 plus or minus 3 days | Serious Adverse Event (SAE) were classified by MedDRA System Organ Class (SOC). An SAE was reported if it met the following criteria and occurred after the first dose of study medication through the end of the study: death throughout study participation; life threatening; requires inpatient hospitalization or prolongation of existing hospitalization during the period of protocol defined surveillance; results in congenital anomaly or birth defect; results in a persistent or significant disability; and an event considered serious by the PI. |
Countries
Canada, United States
Participant flow
Recruitment details
Patients were recruited from the emergency department, hospital, physician's office or clinical care unit. Children of both sexes and all races were included. The recruitment period was January 2007 through May 2010.
Participants by arm
| Arm | Count |
|---|---|
| Cohort IA 12 - 23 months of age, 30 mg | 12 |
| Cohort IB 12 - 23 months of age, 3.5 mg/kg body weight | 3 |
| Cohort IIA 9 - 11 months of age, 3 mg/kg body weight | 7 |
| Cohort IIB 9 to 11 months of age, 3.5 mg/kg body weight | 8 |
| Cohort III 6 to 8 months of age, 3 mg/kg body weight | 24 |
| Cohort IV 3 to 5 months of age, 3 mg/kg body weight | 10 |
| Cohort V 0 to 2 months of age, 3 mg/kg body weight | 23 |
| Total | 87 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 1 | 2 | 2 | 3 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 0 | 0 | 1 | 1 |
Baseline characteristics
| Characteristic | Cohort IA | Cohort IB | Cohort IIA | Cohort IIB | Cohort III | Cohort IV | Total | Cohort V |
|---|---|---|---|---|---|---|---|---|
| Age, Customized | 12 Participants | 3 Participants | 7 Participants | 8 Participants | 24 Participants | 10 Participants | 87 Participants | 23 Participants |
| Region of Enrollment United States | 12 participants | 3 participants | 7 participants | 8 participants | 24 participants | 10 participants | 87 participants | 23 participants |
| Sex: Female, Male Female | 3 Participants | 1 Participants | 3 Participants | 6 Participants | 13 Participants | 2 Participants | 36 Participants | 8 Participants |
| Sex: Female, Male Male | 9 Participants | 2 Participants | 4 Participants | 2 Participants | 11 Participants | 8 Participants | 51 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 8 / 12 | 1 / 3 | 3 / 7 | 6 / 8 | 18 / 24 | 3 / 10 | 14 / 23 |
| serious Total, serious adverse events | 2 / 12 | 0 / 3 | 1 / 7 | 2 / 8 | 2 / 24 | 1 / 10 | 0 / 23 |
Outcome results
Primary
Oseltamivir Carboxylate AUC12 (Area Under the Curve).
The oseltamivir carboxylate AUC12 was derived from a series of five blood draws over 10 to 12 hours.
Time frame: Day 3 of drug administration
Population: Subjects that received 3 days study drug administration and had successful PK draws on study day 3.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort IA | Oseltamivir Carboxylate AUC12 (Area Under the Curve). | AUC12 > or =7700 | 0 participants |
| Cohort IA | Oseltamivir Carboxylate AUC12 (Area Under the Curve). | AUC12 > or = 2660 and <7700 | 4 participants |
| Cohort IA | Oseltamivir Carboxylate AUC12 (Area Under the Curve). | AUC12 <2660 | 6 participants |
| Cohort IB | Oseltamivir Carboxylate AUC12 (Area Under the Curve). | AUC12 > or = 2660 and <7700 | 2 participants |
| Cohort IB | Oseltamivir Carboxylate AUC12 (Area Under the Curve). | AUC12 > or =7700 | 0 participants |
| Cohort IB | Oseltamivir Carboxylate AUC12 (Area Under the Curve). | AUC12 <2660 | 1 participants |
| Cohort IIA | Oseltamivir Carboxylate AUC12 (Area Under the Curve). | AUC12 > or = 2660 and <7700 | 3 participants |
| Cohort IIA | Oseltamivir Carboxylate AUC12 (Area Under the Curve). | AUC12 <2660 | 3 participants |
| Cohort IIA | Oseltamivir Carboxylate AUC12 (Area Under the Curve). | AUC12 > or =7700 | 0 participants |
| Cohort IIB | Oseltamivir Carboxylate AUC12 (Area Under the Curve). | AUC12 <2660 | 0 participants |
| Cohort IIB | Oseltamivir Carboxylate AUC12 (Area Under the Curve). | AUC12 > or = 2660 and <7700 | 7 participants |
| Cohort IIB | Oseltamivir Carboxylate AUC12 (Area Under the Curve). | AUC12 > or =7700 | 0 participants |
| Cohort III | Oseltamivir Carboxylate AUC12 (Area Under the Curve). | AUC12 > or = 2660 and <7700 | 19 participants |
| Cohort III | Oseltamivir Carboxylate AUC12 (Area Under the Curve). | AUC12 <2660 | 2 participants |
| Cohort III | Oseltamivir Carboxylate AUC12 (Area Under the Curve). | AUC12 > or =7700 | 1 participants |
| Cohort IV | Oseltamivir Carboxylate AUC12 (Area Under the Curve). | AUC12 <2660 | 0 participants |
| Cohort IV | Oseltamivir Carboxylate AUC12 (Area Under the Curve). | AUC12 > or =7700 | 0 participants |
| Cohort IV | Oseltamivir Carboxylate AUC12 (Area Under the Curve). | AUC12 > or = 2660 and <7700 | 10 participants |
| Cohort V | Oseltamivir Carboxylate AUC12 (Area Under the Curve). | AUC12 > or =7700 | 3 participants |
| Cohort V | Oseltamivir Carboxylate AUC12 (Area Under the Curve). | AUC12 > or = 2660 and <7700 | 13 participants |
| Cohort V | Oseltamivir Carboxylate AUC12 (Area Under the Curve). | AUC12 <2660 | 3 participants |
Secondary
Correlation of Clearance of Viral RNA by Culture With Pharmacokinetic Parameters by Cohort
The Spearman coefficient and the p-values were computed between the clearance of Viral RNA and Oseltamivir Carboxylate Area under the curve from 0 to 12 hours (AUC0-12)
Time frame: Day to negative viral load for subjects positive at baseline
Population: Subjects included in this analysis are those who had positive culture at baseline (day 0) and had a negative culture on one of the following study visit days: Day 3, Day 5 or Day 10. Culture was obtained from a a nasal swab. Subjects also would have had evaluable PK samples on study day 3.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort IA | Correlation of Clearance of Viral RNA by Culture With Pharmacokinetic Parameters by Cohort | 0.67 Spearman coefficient |
| Cohort IB | Correlation of Clearance of Viral RNA by Culture With Pharmacokinetic Parameters by Cohort | NA Spearman coefficient |
| Cohort IIA | Correlation of Clearance of Viral RNA by Culture With Pharmacokinetic Parameters by Cohort | 0.40 Spearman coefficient |
| Cohort IIB | Correlation of Clearance of Viral RNA by Culture With Pharmacokinetic Parameters by Cohort | 0.62 Spearman coefficient |
| Cohort III | Correlation of Clearance of Viral RNA by Culture With Pharmacokinetic Parameters by Cohort | 0.09 Spearman coefficient |
| Cohort IV | Correlation of Clearance of Viral RNA by Culture With Pharmacokinetic Parameters by Cohort | 0.30 Spearman coefficient |
| Cohort V | Correlation of Clearance of Viral RNA by Culture With Pharmacokinetic Parameters by Cohort | 0.01 Spearman coefficient |
p-value: 0.96Spearman Correlation
p-value: 0.07Spearman Correlation
p-value: 0.6Spearman Correlation
p-value: 0.27Spearman Correlation
p-value: 0.77Spearman Correlation
p-value: 0.47Spearman Correlation
Secondary
Correlation of Clearance of Viral RNA by Polymerase Chain Reaction (PCR) to Pharmacokinetic Parameters by Cohort.
The Spearman coefficient and the p-values were computed between the clearance of viral RNA and oseltamivir carboxylate Area Under the Curve from 0 to 12 hours (AUC 0-12)
Time frame: From date of enrollment until the date of first documented absence of viral load by culture, assessed up to 10 days after enrollment.
Population: Subjects included in this analysis are those who had viral loads at baseline (day 0) and had a non-detectable viral load on one of the following study visit days: day 3, day 5, or day 10. Virus was obtained from a nasal swab. Subjects also would have had evaluable PK samples on study day 3.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort IA | Correlation of Clearance of Viral RNA by Polymerase Chain Reaction (PCR) to Pharmacokinetic Parameters by Cohort. | AUC0-12 (hr*ng/mL) unit: Spearman Coefficient | 0.57 correlation measure |
| Cohort IA | Correlation of Clearance of Viral RNA by Polymerase Chain Reaction (PCR) to Pharmacokinetic Parameters by Cohort. | AUC0-12 (hr*ng/mL) unit: P value | 0.08 correlation measure |
| Cohort IB | Correlation of Clearance of Viral RNA by Polymerase Chain Reaction (PCR) to Pharmacokinetic Parameters by Cohort. | AUC0-12 (hr*ng/mL) unit: Spearman Coefficient | NA correlation measure |
| Cohort IB | Correlation of Clearance of Viral RNA by Polymerase Chain Reaction (PCR) to Pharmacokinetic Parameters by Cohort. | AUC0-12 (hr*ng/mL) unit: P value | NA correlation measure |
| Cohort IIA | Correlation of Clearance of Viral RNA by Polymerase Chain Reaction (PCR) to Pharmacokinetic Parameters by Cohort. | AUC0-12 (hr*ng/mL) unit: Spearman Coefficient | 0.21 correlation measure |
| Cohort IIA | Correlation of Clearance of Viral RNA by Polymerase Chain Reaction (PCR) to Pharmacokinetic Parameters by Cohort. | AUC0-12 (hr*ng/mL) unit: P value | 0.79 correlation measure |
| Cohort IIB | Correlation of Clearance of Viral RNA by Polymerase Chain Reaction (PCR) to Pharmacokinetic Parameters by Cohort. | AUC0-12 (hr*ng/mL) unit: P value | 0.04 correlation measure |
| Cohort IIB | Correlation of Clearance of Viral RNA by Polymerase Chain Reaction (PCR) to Pharmacokinetic Parameters by Cohort. | AUC0-12 (hr*ng/mL) unit: Spearman Coefficient | 0.90 correlation measure |
| Cohort III | Correlation of Clearance of Viral RNA by Polymerase Chain Reaction (PCR) to Pharmacokinetic Parameters by Cohort. | AUC0-12 (hr*ng/mL) unit: P value | 0.30 correlation measure |
| Cohort III | Correlation of Clearance of Viral RNA by Polymerase Chain Reaction (PCR) to Pharmacokinetic Parameters by Cohort. | AUC0-12 (hr*ng/mL) unit: Spearman Coefficient | 0.28 correlation measure |
| Cohort IV | Correlation of Clearance of Viral RNA by Polymerase Chain Reaction (PCR) to Pharmacokinetic Parameters by Cohort. | AUC0-12 (hr*ng/mL) unit: Spearman Coefficient | 0.04 correlation measure |
| Cohort IV | Correlation of Clearance of Viral RNA by Polymerase Chain Reaction (PCR) to Pharmacokinetic Parameters by Cohort. | AUC0-12 (hr*ng/mL) unit: P value | 0.93 correlation measure |
| Cohort V | Correlation of Clearance of Viral RNA by Polymerase Chain Reaction (PCR) to Pharmacokinetic Parameters by Cohort. | AUC0-12 (hr*ng/mL) unit: P value | 0.77 correlation measure |
| Cohort V | Correlation of Clearance of Viral RNA by Polymerase Chain Reaction (PCR) to Pharmacokinetic Parameters by Cohort. | AUC0-12 (hr*ng/mL) unit: Spearman Coefficient | 0.07 correlation measure |
Secondary
Incidence of All Serious Adverse Events by Cohort and System Organ Class (SOC)
Serious Adverse Event (SAE) were classified by MedDRA System Organ Class (SOC). An SAE was reported if it met the following criteria and occurred after the first dose of study medication through the end of the study: death throughout study participation; life threatening; requires inpatient hospitalization or prolongation of existing hospitalization during the period of protocol defined surveillance; results in congenital anomaly or birth defect; results in a persistent or significant disability; and an event considered serious by the PI.
Time frame: Duration of study, from receipt of the first dose of study drug and continuing through study visit Day 30 plus or minus 3 days
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort IA | Incidence of All Serious Adverse Events by Cohort and System Organ Class (SOC) | Immune System Disorders | 0 Participants |
| Cohort IA | Incidence of All Serious Adverse Events by Cohort and System Organ Class (SOC) | General Disorders & Administration Site Conditions | 0 Participants |
| Cohort IA | Incidence of All Serious Adverse Events by Cohort and System Organ Class (SOC) | Infections and Infestations | 2 Participants |
| Cohort IA | Incidence of All Serious Adverse Events by Cohort and System Organ Class (SOC) | Total | 2 Participants |
| Cohort IA | Incidence of All Serious Adverse Events by Cohort and System Organ Class (SOC) | Investigations | 0 Participants |
| Cohort IA | Incidence of All Serious Adverse Events by Cohort and System Organ Class (SOC) | Respiratory, thoracic & mediastinal disorders | 0 Participants |
| Cohort IB | Incidence of All Serious Adverse Events by Cohort and System Organ Class (SOC) | Total | 0 Participants |
| Cohort IB | Incidence of All Serious Adverse Events by Cohort and System Organ Class (SOC) | Infections and Infestations | 0 Participants |
| Cohort IB | Incidence of All Serious Adverse Events by Cohort and System Organ Class (SOC) | Respiratory, thoracic & mediastinal disorders | 0 Participants |
| Cohort IB | Incidence of All Serious Adverse Events by Cohort and System Organ Class (SOC) | General Disorders & Administration Site Conditions | 0 Participants |
| Cohort IB | Incidence of All Serious Adverse Events by Cohort and System Organ Class (SOC) | Investigations | 0 Participants |
| Cohort IB | Incidence of All Serious Adverse Events by Cohort and System Organ Class (SOC) | Immune System Disorders | 0 Participants |
| Cohort IIA | Incidence of All Serious Adverse Events by Cohort and System Organ Class (SOC) | Investigations | 0 Participants |
| Cohort IIA | Incidence of All Serious Adverse Events by Cohort and System Organ Class (SOC) | Immune System Disorders | 1 Participants |
| Cohort IIA | Incidence of All Serious Adverse Events by Cohort and System Organ Class (SOC) | Respiratory, thoracic & mediastinal disorders | 0 Participants |
| Cohort IIA | Incidence of All Serious Adverse Events by Cohort and System Organ Class (SOC) | Infections and Infestations | 0 Participants |
| Cohort IIA | Incidence of All Serious Adverse Events by Cohort and System Organ Class (SOC) | Total | 1 Participants |
| Cohort IIA | Incidence of All Serious Adverse Events by Cohort and System Organ Class (SOC) | General Disorders & Administration Site Conditions | 0 Participants |
| Cohort IIB | Incidence of All Serious Adverse Events by Cohort and System Organ Class (SOC) | Investigations | 1 Participants |
| Cohort IIB | Incidence of All Serious Adverse Events by Cohort and System Organ Class (SOC) | Total | 2 Participants |
| Cohort IIB | Incidence of All Serious Adverse Events by Cohort and System Organ Class (SOC) | General Disorders & Administration Site Conditions | 0 Participants |
| Cohort IIB | Incidence of All Serious Adverse Events by Cohort and System Organ Class (SOC) | Immune System Disorders | 0 Participants |
| Cohort IIB | Incidence of All Serious Adverse Events by Cohort and System Organ Class (SOC) | Infections and Infestations | 1 Participants |
| Cohort IIB | Incidence of All Serious Adverse Events by Cohort and System Organ Class (SOC) | Respiratory, thoracic & mediastinal disorders | 0 Participants |
| Cohort III | Incidence of All Serious Adverse Events by Cohort and System Organ Class (SOC) | Infections and Infestations | 1 Participants |
| Cohort III | Incidence of All Serious Adverse Events by Cohort and System Organ Class (SOC) | General Disorders & Administration Site Conditions | 1 Participants |
| Cohort III | Incidence of All Serious Adverse Events by Cohort and System Organ Class (SOC) | Investigations | 0 Participants |
| Cohort III | Incidence of All Serious Adverse Events by Cohort and System Organ Class (SOC) | Total | 2 Participants |
| Cohort III | Incidence of All Serious Adverse Events by Cohort and System Organ Class (SOC) | Immune System Disorders | 0 Participants |
| Cohort III | Incidence of All Serious Adverse Events by Cohort and System Organ Class (SOC) | Respiratory, thoracic & mediastinal disorders | 0 Participants |
| Cohort IV | Incidence of All Serious Adverse Events by Cohort and System Organ Class (SOC) | Immune System Disorders | 0 Participants |
| Cohort IV | Incidence of All Serious Adverse Events by Cohort and System Organ Class (SOC) | Infections and Infestations | 0 Participants |
| Cohort IV | Incidence of All Serious Adverse Events by Cohort and System Organ Class (SOC) | General Disorders & Administration Site Conditions | 0 Participants |
| Cohort IV | Incidence of All Serious Adverse Events by Cohort and System Organ Class (SOC) | Investigations | 0 Participants |
| Cohort IV | Incidence of All Serious Adverse Events by Cohort and System Organ Class (SOC) | Respiratory, thoracic & mediastinal disorders | 1 Participants |
| Cohort IV | Incidence of All Serious Adverse Events by Cohort and System Organ Class (SOC) | Total | 1 Participants |
| Cohort V | Incidence of All Serious Adverse Events by Cohort and System Organ Class (SOC) | Respiratory, thoracic & mediastinal disorders | 0 Participants |
| Cohort V | Incidence of All Serious Adverse Events by Cohort and System Organ Class (SOC) | General Disorders & Administration Site Conditions | 0 Participants |
| Cohort V | Incidence of All Serious Adverse Events by Cohort and System Organ Class (SOC) | Immune System Disorders | 0 Participants |
| Cohort V | Incidence of All Serious Adverse Events by Cohort and System Organ Class (SOC) | Infections and Infestations | 0 Participants |
| Cohort V | Incidence of All Serious Adverse Events by Cohort and System Organ Class (SOC) | Investigations | 0 Participants |
| Cohort V | Incidence of All Serious Adverse Events by Cohort and System Organ Class (SOC) | Total | 0 Participants |
Secondary
Incidence of Treatment Emergent AEs and Drug Related AEs by Cohort and Toxicity Grade
Any event considered to be related to the study drug that occurred post first dose of drug administration that was not present at baseline was considered an AE. Expected flu symptoms were not reported as AEs but were collected separately. The Division of AIDS Toxicity Tables (DIAIDS) were used to grade the events.
Time frame: Duration of study, from receipt of the first dose of study drug and continuing through study visit Day 30 plus or minus 3 days
Population: Intention to treat (ITT)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort IA | Incidence of Treatment Emergent AEs and Drug Related AEs by Cohort and Toxicity Grade | Grade V - Death | 0 Participants |
| Cohort IA | Incidence of Treatment Emergent AEs and Drug Related AEs by Cohort and Toxicity Grade | Grade II - Moderate | 0 Participants |
| Cohort IA | Incidence of Treatment Emergent AEs and Drug Related AEs by Cohort and Toxicity Grade | Grade I - Mild | 3 Participants |
| Cohort IA | Incidence of Treatment Emergent AEs and Drug Related AEs by Cohort and Toxicity Grade | Grade IV - Life-threatening | 0 Participants |
| Cohort IA | Incidence of Treatment Emergent AEs and Drug Related AEs by Cohort and Toxicity Grade | Grade III - Severe | 0 Participants |
| Cohort IB | Incidence of Treatment Emergent AEs and Drug Related AEs by Cohort and Toxicity Grade | Grade III - Severe | 0 Participants |
| Cohort IB | Incidence of Treatment Emergent AEs and Drug Related AEs by Cohort and Toxicity Grade | Grade V - Death | 0 Participants |
| Cohort IB | Incidence of Treatment Emergent AEs and Drug Related AEs by Cohort and Toxicity Grade | Grade II - Moderate | 0 Participants |
| Cohort IB | Incidence of Treatment Emergent AEs and Drug Related AEs by Cohort and Toxicity Grade | Grade I - Mild | 0 Participants |
| Cohort IB | Incidence of Treatment Emergent AEs and Drug Related AEs by Cohort and Toxicity Grade | Grade IV - Life-threatening | 0 Participants |
| Cohort IIA | Incidence of Treatment Emergent AEs and Drug Related AEs by Cohort and Toxicity Grade | Grade V - Death | 0 Participants |
| Cohort IIA | Incidence of Treatment Emergent AEs and Drug Related AEs by Cohort and Toxicity Grade | Grade I - Mild | 0 Participants |
| Cohort IIA | Incidence of Treatment Emergent AEs and Drug Related AEs by Cohort and Toxicity Grade | Grade III - Severe | 0 Participants |
| Cohort IIA | Incidence of Treatment Emergent AEs and Drug Related AEs by Cohort and Toxicity Grade | Grade IV - Life-threatening | 0 Participants |
| Cohort IIA | Incidence of Treatment Emergent AEs and Drug Related AEs by Cohort and Toxicity Grade | Grade II - Moderate | 0 Participants |
| Cohort IIB | Incidence of Treatment Emergent AEs and Drug Related AEs by Cohort and Toxicity Grade | Grade II - Moderate | 0 Participants |
| Cohort IIB | Incidence of Treatment Emergent AEs and Drug Related AEs by Cohort and Toxicity Grade | Grade III - Severe | 0 Participants |
| Cohort IIB | Incidence of Treatment Emergent AEs and Drug Related AEs by Cohort and Toxicity Grade | Grade IV - Life-threatening | 0 Participants |
| Cohort IIB | Incidence of Treatment Emergent AEs and Drug Related AEs by Cohort and Toxicity Grade | Grade V - Death | 0 Participants |
| Cohort IIB | Incidence of Treatment Emergent AEs and Drug Related AEs by Cohort and Toxicity Grade | Grade I - Mild | 0 Participants |
| Cohort III | Incidence of Treatment Emergent AEs and Drug Related AEs by Cohort and Toxicity Grade | Grade III - Severe | 0 Participants |
| Cohort III | Incidence of Treatment Emergent AEs and Drug Related AEs by Cohort and Toxicity Grade | Grade IV - Life-threatening | 0 Participants |
| Cohort III | Incidence of Treatment Emergent AEs and Drug Related AEs by Cohort and Toxicity Grade | Grade II - Moderate | 0 Participants |
| Cohort III | Incidence of Treatment Emergent AEs and Drug Related AEs by Cohort and Toxicity Grade | Grade I - Mild | 3 Participants |
| Cohort III | Incidence of Treatment Emergent AEs and Drug Related AEs by Cohort and Toxicity Grade | Grade V - Death | 0 Participants |
| Cohort IV | Incidence of Treatment Emergent AEs and Drug Related AEs by Cohort and Toxicity Grade | Grade V - Death | 0 Participants |
| Cohort IV | Incidence of Treatment Emergent AEs and Drug Related AEs by Cohort and Toxicity Grade | Grade I - Mild | 0 Participants |
| Cohort IV | Incidence of Treatment Emergent AEs and Drug Related AEs by Cohort and Toxicity Grade | Grade IV - Life-threatening | 0 Participants |
| Cohort IV | Incidence of Treatment Emergent AEs and Drug Related AEs by Cohort and Toxicity Grade | Grade III - Severe | 0 Participants |
| Cohort IV | Incidence of Treatment Emergent AEs and Drug Related AEs by Cohort and Toxicity Grade | Grade II - Moderate | 0 Participants |
| Cohort V | Incidence of Treatment Emergent AEs and Drug Related AEs by Cohort and Toxicity Grade | Grade V - Death | 0 Participants |
| Cohort V | Incidence of Treatment Emergent AEs and Drug Related AEs by Cohort and Toxicity Grade | Grade III - Severe | 0 Participants |
| Cohort V | Incidence of Treatment Emergent AEs and Drug Related AEs by Cohort and Toxicity Grade | Grade II - Moderate | 0 Participants |
| Cohort V | Incidence of Treatment Emergent AEs and Drug Related AEs by Cohort and Toxicity Grade | Grade IV - Life-threatening | 0 Participants |
| Cohort V | Incidence of Treatment Emergent AEs and Drug Related AEs by Cohort and Toxicity Grade | Grade I - Mild | 1 Participants |
Secondary
Incidence of Treatment Emergent AEs and Drug Related AEs by Cohort Leading to Discontinuation of Study Medication
Study drug was administered for 5 days; any event that occurred prior to the last dose of study medication that was considered related to an AE and that caused the subject to stop taking study drug.
Time frame: Duration of study, from receipt of the first dose of study drug and continuing through study visit Day 5 plus or minus 1 day
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort IA | Incidence of Treatment Emergent AEs and Drug Related AEs by Cohort Leading to Discontinuation of Study Medication | 0 events |
| Cohort IB | Incidence of Treatment Emergent AEs and Drug Related AEs by Cohort Leading to Discontinuation of Study Medication | 0 events |
| Cohort IIA | Incidence of Treatment Emergent AEs and Drug Related AEs by Cohort Leading to Discontinuation of Study Medication | 1 events |
| Cohort IIB | Incidence of Treatment Emergent AEs and Drug Related AEs by Cohort Leading to Discontinuation of Study Medication | 0 events |
| Cohort III | Incidence of Treatment Emergent AEs and Drug Related AEs by Cohort Leading to Discontinuation of Study Medication | 0 events |
| Cohort IV | Incidence of Treatment Emergent AEs and Drug Related AEs by Cohort Leading to Discontinuation of Study Medication | 0 events |
| Cohort V | Incidence of Treatment Emergent AEs and Drug Related AEs by Cohort Leading to Discontinuation of Study Medication | 0 events |
Secondary
Number and Characteristics of Adverse Events (AEs) Described as Neurological Events.
Any neurological event that occurred post first dose of drug administration that was not present at baseline was considered an AE. Expected flu symptoms were not reported as AEs but were collected separately.
Time frame: Duration of study, from receipt of the first dose of study drug and continuing through study visit Day 30 plus or minus 3 days.
Population: Intention to treat (ITT)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort IA | Number and Characteristics of Adverse Events (AEs) Described as Neurological Events. | Event - Lethargy | 0 participants |
| Cohort IA | Number and Characteristics of Adverse Events (AEs) Described as Neurological Events. | Event - Tremor | 0 participants |
| Cohort IB | Number and Characteristics of Adverse Events (AEs) Described as Neurological Events. | Event - Lethargy | 0 participants |
| Cohort IB | Number and Characteristics of Adverse Events (AEs) Described as Neurological Events. | Event - Tremor | 1 participants |
| Cohort IIA | Number and Characteristics of Adverse Events (AEs) Described as Neurological Events. | Event - Lethargy | 0 participants |
| Cohort IIA | Number and Characteristics of Adverse Events (AEs) Described as Neurological Events. | Event - Tremor | 0 participants |
| Cohort IIB | Number and Characteristics of Adverse Events (AEs) Described as Neurological Events. | Event - Lethargy | 0 participants |
| Cohort IIB | Number and Characteristics of Adverse Events (AEs) Described as Neurological Events. | Event - Tremor | 0 participants |
| Cohort III | Number and Characteristics of Adverse Events (AEs) Described as Neurological Events. | Event - Lethargy | 1 participants |
| Cohort III | Number and Characteristics of Adverse Events (AEs) Described as Neurological Events. | Event - Tremor | 0 participants |
| Cohort IV | Number and Characteristics of Adverse Events (AEs) Described as Neurological Events. | Event - Lethargy | 0 participants |
| Cohort IV | Number and Characteristics of Adverse Events (AEs) Described as Neurological Events. | Event - Tremor | 0 participants |
| Cohort V | Number and Characteristics of Adverse Events (AEs) Described as Neurological Events. | Event - Tremor | 0 participants |
| Cohort V | Number and Characteristics of Adverse Events (AEs) Described as Neurological Events. | Event - Lethargy | 0 participants |
Secondary
Overall Reported Adverse Events (AEs) Thought to be Associated With Study Therapy.
Any event considered associated with drug that occurred post first dose of drug administration that was not present at baseline was considered an AE. Expected flu symptoms were not reported as AEs but were collected separately.
Time frame: Duration of study, from receipt of the first dose of study drug and continuing through study visit Day 30 plus or minus 3 days.
Population: Intention to treat (ITT)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort IA | Overall Reported Adverse Events (AEs) Thought to be Associated With Study Therapy. | Event - Rash | 0 participants |
| Cohort IA | Overall Reported Adverse Events (AEs) Thought to be Associated With Study Therapy. | Event - Dermatitis Diaper | 0 participants |
| Cohort IA | Overall Reported Adverse Events (AEs) Thought to be Associated With Study Therapy. | Event - Vomiting | 3 participants |
| Cohort IB | Overall Reported Adverse Events (AEs) Thought to be Associated With Study Therapy. | Event - Dermatitis Diaper | 0 participants |
| Cohort IB | Overall Reported Adverse Events (AEs) Thought to be Associated With Study Therapy. | Event - Vomiting | 0 participants |
| Cohort IB | Overall Reported Adverse Events (AEs) Thought to be Associated With Study Therapy. | Event - Rash | 0 participants |
| Cohort IIA | Overall Reported Adverse Events (AEs) Thought to be Associated With Study Therapy. | Event - Rash | 0 participants |
| Cohort IIA | Overall Reported Adverse Events (AEs) Thought to be Associated With Study Therapy. | Event - Vomiting | 0 participants |
| Cohort IIA | Overall Reported Adverse Events (AEs) Thought to be Associated With Study Therapy. | Event - Dermatitis Diaper | 0 participants |
| Cohort IIB | Overall Reported Adverse Events (AEs) Thought to be Associated With Study Therapy. | Event - Dermatitis Diaper | 0 participants |
| Cohort IIB | Overall Reported Adverse Events (AEs) Thought to be Associated With Study Therapy. | Event - Vomiting | 0 participants |
| Cohort IIB | Overall Reported Adverse Events (AEs) Thought to be Associated With Study Therapy. | Event - Rash | 0 participants |
| Cohort III | Overall Reported Adverse Events (AEs) Thought to be Associated With Study Therapy. | Event - Rash | 0 participants |
| Cohort III | Overall Reported Adverse Events (AEs) Thought to be Associated With Study Therapy. | Event - Vomiting | 2 participants |
| Cohort III | Overall Reported Adverse Events (AEs) Thought to be Associated With Study Therapy. | Event - Dermatitis Diaper | 1 participants |
| Cohort IV | Overall Reported Adverse Events (AEs) Thought to be Associated With Study Therapy. | Event - Rash | 0 participants |
| Cohort IV | Overall Reported Adverse Events (AEs) Thought to be Associated With Study Therapy. | Event - Dermatitis Diaper | 0 participants |
| Cohort IV | Overall Reported Adverse Events (AEs) Thought to be Associated With Study Therapy. | Event - Vomiting | 0 participants |
| Cohort V | Overall Reported Adverse Events (AEs) Thought to be Associated With Study Therapy. | Event - Vomiting | 0 participants |
| Cohort V | Overall Reported Adverse Events (AEs) Thought to be Associated With Study Therapy. | Event - Dermatitis Diaper | 0 participants |
| Cohort V | Overall Reported Adverse Events (AEs) Thought to be Associated With Study Therapy. | Event - Rash | 1 participants |