HIV Infection
Conditions
Keywords
pediatrics, HIV, protease inhibitors, ritonavir, fosamprenavir, LEXIVA, AGENERASE, amprenavir
Brief summary
This is a 48-week study to collect additional information on the safety, tolerability, pharmacokinetics, and antiviral activity of an investigational regimen (course of therapy) including FDA approved HIV drugs in HIV-infected patients 2 - 18 years old.
Detailed description
A 48 Week, Phase II, Open-label, Multi-Cohort, Multicenter Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Antiviral Activity of GW433908/Ritonavir QD and GW433908/Ritonavir BID when Administered to HIV-1 Infected, Antiretroviral Naive and Experience Pediatric Subjects 2 to 18 Years Old ViiV Healthcare is the new sponsor of this study, and GlaxoSmithKline is in the process of updating systems to reflect the change in sponsorship
Interventions
DRUGritonavir
ritonavir oral capsules or oral solution
DRUGfosamprenavir
fosamprenavir oral suspension or tablet
Sponsors
ViiV Healthcare
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to 18 Years
Healthy volunteers
No
Inclusion criteria
* Inclusion Criteria: * Male or females 2 to 18 years of age * A female is eligible to enter and participate in this study if she is of: * a. non-childbearing potential (i.e., physiologically incapable of becoming pregnant, including any female who is pre-menarchial); or, * b. child-bearing potential with a negative serum pregnancy test at screen, a negative urine pregnancy test on Day 1 and who agrees to use one of the following methods of contraception (any contraception method must be used consistently and correctly, i.e., in accordance with both the product label and the instructions of a physician). Note: hormonal contraceptives are not considered a sufficient form of contraceptive for this study. * Complete abstinence from intercourse from 2 weeks prior to administration of study drugs, throughout the study and for 2 weeks after discontinuation of all study medications. Should a female subject of childbearing potential decide to become sexually active during the course of the study, she must be counselled and be willing to use one of the methods listed below: * Double barrier contraception (male condom/spermicide, male condom/diaphragm, diaphragm/spermicide) * Any intrauterine device (IUD) with published data showing that the expected failure rate is less than 1% per year (not all IUDs meet this criterion) * Any other method with published data showing that the lowest expected failure rate for that method is less than 1% per year. All subjects participating in this study should be counselled on the practice of safe/safer sex. * Parent or legal guardian (and subject whenever possible) has the ability to understand and provide written informed consent for the subject to participate in the trial. Verbal witnessed assent must be obtained from the subject whenever possible. * Screening plasma HIV-1 RNA \> or =400copies/mL. * Subject's who, in the investigator's opinion, and following resistance testing where appropriate, are able to construct an active NRTI backbone regimen consisting of 2 NRTIs. * Subjects must meet one of the following criteria: * ART-naïve subjects are defined as having had \< 4 weeks (28 days) therapy with an NRTI, no previous therapy with an NNRTI and \< 1 week therapy with an HIV PI. * ART-experienced subjects are defined as having had greater than 4 weeks (28 days) therapy with any NRTI(s) and any length of therapy with any NNRTI(s) and/or a PI. PI-experienced subjects will be eligible if they have previously been treated with \< three PIs, excluding AGENERASE. Prior therapy with a RTV boosted PI regimen will be considered as only 1 prior PI as long as the RTV dose was below that recommended for use of RTV as an antiretroviral agent. This specific criterion is not applicable to subjects in screening and/or enrolling after approval of Amendment No. 4. - For subjects screening and/or enrolling after the approval of Amendment No.4, PI naive subjects are defined as ART experienced subjects having less than one week of therapy with a PI and no prior experience with AGENERASE. Prior treatment with NNRTIs and NRTIs is permitted (however, subjects will NOT be permitted to receive concurrent NNRTI therapy while participating in this study) *
Exclusion criteria
* Prior history of having received amprenavir. * Use of non-nucleoside reverse transcriptase inhibitor (NNRTI) therapy within 14 days of study Day 1 or anticipated need for concurrent NNRTI therapy during the study period. * Have had an AIDS defining illness (acute CDC Category C event) within 28 days of screening. * Pregnant or lactating. * Non-nucleoside reverse transcriptase inhibitor therapy within 14 days prior to study drug administration or anticipated need for concurrent NNRTI therapy during the study period. * Subjects who, in the investigator's opinion, are not able to comply with the requirements of the study. * An acute CDC Category C event (per 1993/1994 classification) and/or serious bacterial infection(s) within 28 days prior to study drug administration. * Presence of a malabsorption syndrome or other gastrointestinal dysfunction which might interfere with drug absorption or render the subject unable to take oral medication. * Presence of any serious medical condition (e.g., hemoglobinopathy, chronic anemia,diabetes, cardiac dysfunction and hepatitis) which, in the opinion of the investigator, might compromise the safety of the subject. * Current grade 2 or higher serum lipase within 28 days prior to study drug administration and/or history of clinically relevant pancreatitis within the previous 6 months. - Grade 3 or 4 transaminase levels (ALT and/or AST) within 28 days prior to study drug administration and/or clinically relevant hepatitis within the previous 6 months. * Treatment with radiation therapy or cytotoxic chemotherapeutic agents within 28 days of study drug administration or an anticipated need for such treatment within the study period. * Treatment with immunomodulating agents (e.g., systemic corticosteroids, interleukins, interferons) or any agent with known anti-HIV activity (e.g., hydroxyurea or foscarnet) within 28 days of study drug administration. * Treatment with any of the following medications within 28 days prior to receiving study medication or the anticipated need during the study: * Amiodarone, astemizole, bepridil, bupropion, cisapride, clorazepate, clozapine, diazepin, dihydroergotamine, encainide, ergonovine, ergotamine, estazolam, flecainide, flurazepam, lovastatin, meperidine, methylergonovine, midazolam, pimozide, piroxicam, propafenone, propoxyphene, quinidine, rifabutin, simvastatin, terfenadine, triazolam, zolpidem (these drugs have been excluded for safety reasons). * Carbamazepine, dexamethasone, phenobarbital, phenytoin, primidone, rifampin, St Johns Wort (these drugs have been excluded because they have the potential to decrease plasma protease inhibitor concentrations) - Systemic chemotherapeutic agents * Treatment with other investigational drugs/therapies (note: treatments available through a Treatment IND or other expanded-access mechanism will be evaluated on a case-by-case basis in consultation with the sponsor) within 28 days prior to study drug administration * History of drug or other allergy which, in the opinion of the investigator, contraindicates participation in the trial or known hypersensitivity to any study medications (e.g., documented hypersensitivity to a nucleoside analogue).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Least Squares Mean of Plasma APV Parameter: Ctau | 0, 1, 2, 4, 8, 12, and 24 hours post dosing at Week 4. | A blood sample was drawn on Week 4 over 24 hours (at 0, 1, 2, 4, 8, 12, and 24 hours post dosing). Ratio of geometric least squares mean (90% CI) are presented. Ctau=trough concentration. PK Parameters for QD and BID are compared with Historical adult data. Least squares mean (LSM) are the group means after having controlled for a covariate (i.e., holding it constant at some typical value of the covariate, such as its mean value). LSM is calculated by taking the average of the means within a treatment. |
| Geometric Mean of Steady State Plasma APV Parameter: CL/F | 0, 1, 2, 4, 8, 12, and 24 hours post dosing at Week 4 | Geometric mean is a type of average that indicates the central tendency of a set of values and is calculated by multiplying all the numbers in a set, and then taking the nth root of the resulting product. CL/F=apparent plasma clearance. |
| Geometric Mean of Steady State Plasma APV Parameter: t1/2 | 0, 1, 2, 4, 8, 12, and 24 hours post dosing at Week 4 | Geometric mean is a type of average that indicates the central tendency of a set of values and is calculated by multiplying all the numbers in a set, and then taking the nth root of the resulting product. t1/2=elimination half-life. t1/2=elimination half-life. |
| Least Squares Mean of Plasma APV Parameter: AUC0-tau | 0, 1, 2, 4, 8, 12, and 24 hours post dosing at Week 4 | A blood sample was drawn on Week 4 over 24 hours (at 0, 1, 2, 4, 8, 12, and 24 hours post dosing). Ratio of geometric least squares mean (90% CI) are presented. Ctau=trough concentration. PK Parameters for QD and BID are compared with Historical adult data. Least squares mean (LSM) are the group means after having controlled for a covariate (i.e., holding it constant at some typical value of the covariate, such as its mean value). LSM is calculated by taking the average of the means within a treatment. |
| Least Squares Mean of Plasma APV Parameter: Cmax | 0, 1, 2, 4, 8, 12, and 24 hours post dosing at Week 4. | A blood sample was drawn on Week 4 over 24 hours (at 0, 1, 2, 4, 8, 12, and 24 hours post dosing). Ratio of geometric least squares mean (90% CI) are presented. Ctau=trough concentration. PK Parameters for QD and BID are compared with Historical adult data. Least squares mean (LSM) are the group means after having controlled for a covariate (i.e., holding it constant at some typical value of the covariate, such as its mean value). LSM is calculated by taking the average of the means within a treatment. |
| Number of Participants Who Discontinued Treatment Due to Adverse Events | Baseline through end of study (at least Week 168) | The number of participants who prematurely discontinued study drug due to adverse events was tabulated. Data are summarized by individual adverse event. |
| Number of Participants With Any Drug-related Grade 2 to 4 Adverse Event | Baseline through end of study (at least Week 168) | The number of participants with drug-related adverse events coded as Grade 2 (mild), Grade 3 (severe), or Grade 4 (life-threatening). |
| Number of Participants With Grade 3 or 4 Treatment-emergent Laboratory Abnormalities | Baseline through end of study (at least Week 168) | The number of participants with Grade 3 (severe) or Grade 4 (life-threatening) laboratory abnormalities while on study treatment. |
| Geometric Mean of Steady State Plasma Amprenavir (APV) Parameter: AUC(0-tau) | 0, 1, 2, 4, 8, 12, and 24 hours post dosing at Week 4 | Geometric mean is a type of average that indicates the central tendency of a set of values and is calculated by multiplying all the numbers in a set, and then taking the nth root of the resulting product. AUC(0-tau)=area under the concentration curve from time 0 to tau. |
| Geometric Mean of Steady State Plasma APV Parameter: Cmax | 0, 1, 2, 4, 8, 12, and 24 hours post dosing at Week 4 | Geometric mean is a type of average that indicates the central tendency of a set of values and is calculated by multiplying all the numbers in a set, and then taking the nth root of the resulting product. Cmax= concentration maximum. |
| Median Steady State Plasma APV Tmax | 0, 1, 2, 4, 8, 12, and 24 hours post dosing at Week 4 | tmax: time after administration of the drug when maximum concentration is reached |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Change From Baseline HIV-1 RNA Values at Weeks 12, 48, 96, and 168 Visits | Baseline and Weeks 12, 48, 96, and 168 | A blood sample was drawn to determine the amount of HIV-1 RNA virus in copies/mL at Weeks 12, 24, 48, 96, and 168. Change from Baseline was defined as the HIV-1 RNA level at Weeks 12, 24, 48, 96, and 168 minus the HIV-1 RNA level at Baseline. |
| Median Change From Baseline in CD4+ Values at Week 12, 48, 96, and 168 Visits | Baseline and Weeks 12, 48, 96, and 168 | A blood sample was drawn to determine the CD4+ cell count at Weeks 24, 48, 96, and 168. Change from Baseline was defined as the CD4+ cell count at Weeks 24, 48, 96, and 168 minus the CD4+ cell count at Baseline. |
| Number of Participants With APV Resistance Associated HIV-1 RNA Genotypic Mutations and Phenotypic Resistance at Time of Virologic Failure Not Present at Baseline | Time of virologic failure | A blood sample was drawn for participants failing to respond to therapy, and the mutations present in the virus were identified. For each participant, the mutations found at the time of failure were compared with any mutations found in the blood sample at baseline. New mutations that developed at the time of virologic failure were tabulated by drug class. Virologic failure is defined as HIV-1 RNA greater than or equal to 400 copies/mL. |
| Percentage of Participants With HIV-1 RNA <400 Copies Per mL at Weeks 12, 48, 96, and 168 (Time to Loss of Virologic Response [TLOVR] Analysis) | Weeks 12, 48, 96, and 168 | A blood sample was drawn to determine the amount of HIV-1 RNA virus in copies per milliliter (mL) at Weeks 12, 48, 96, and 196. The percentage of participants with HIV-1 RNA \<400 copies/mL at Weeks 12, 48, 96, 168 was determined by the TLOVR algorithm with stratification by the six randomization strata. TLOVR analysis categorizes participants by treatment response. Responders were participants with confirmed viral load \<400copies/mL on two consecutive visits. |
Countries
Canada, Italy, Netherlands, Portugal, Romania, Spain, United States
Participant flow
Recruitment details
Cohorts were recruited in parallel. All Age Cohorts were given the same treatment.
Pre-assignment details
The overall study population consisted of 69 participants presented as Overall Fosamprenavir (FPV)/ritonavir (RTV) in the Participant Flow section. Furthermore, the Overall FPV/RTV participants are stratified by age cohorts (Arms 2-4).
Participants by arm
| Arm | Count |
|---|---|
| FPV/RTV Fosamprenavir (FPV) 700 mg tablets or 50 mg/mL oral suspension/ritonavir (RTV) 100 mg capsules or 80 mg/mL oral solution once daily (QD) | 69 |
| Total | 69 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 12 | 3 | 2 | 7 |
| Overall Study | Change of formulation | 2 | 2 | 0 | 0 |
| Overall Study | Insufficient CD4 response | 1 | 0 | 1 | 0 |
| Overall Study | Lack of Efficacy | 9 | 2 | 3 | 4 |
| Overall Study | Lost to Follow-up | 4 | 2 | 0 | 2 |
| Overall Study | Medication adherence/compliance problems | 8 | 2 | 1 | 5 |
| Overall Study | Non-viability of oral suspension | 1 | 0 | 1 | 0 |
| Overall Study | Pharmacokinetic target not achieved | 2 | 1 | 0 | 1 |
| Overall Study | Poor taste | 2 | 0 | 2 | 0 |
| Overall Study | Pregnancy | 3 | 0 | 0 | 3 |
| Overall Study | Protocol Violation | 2 | 1 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 7 | 0 | 3 | 4 |
Baseline characteristics
| Characteristic | FPV/RTV |
|---|---|
| Age, Continuous | 10.2 years STANDARD_DEVIATION 4.6 |
| Race/Ethnicity, Customized African Heritage | 1 participants |
| Race/Ethnicity, Customized American Hispanic | 8 participants |
| Race/Ethnicity, Customized Black | 24 participants |
| Race/Ethnicity, Customized East and South East Asian | 1 participants |
| Race/Ethnicity, Customized White/Caucasian | 35 participants |
| Sex: Female, Male Female | 39 Participants |
| Sex: Female, Male Male | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 63 / — |
| serious Total, serious adverse events | 19 / — |
Outcome results
Primary
Geometric Mean of Steady State Plasma Amprenavir (APV) Parameter: AUC(0-tau)
Geometric mean is a type of average that indicates the central tendency of a set of values and is calculated by multiplying all the numbers in a set, and then taking the nth root of the resulting product. AUC(0-tau)=area under the concentration curve from time 0 to tau.
Time frame: 0, 1, 2, 4, 8, 12, and 24 hours post dosing at Week 4
Population: The Pharmacokinetic (PK) Parameter Population included all participants who underwent plasma PK sampling and provided full PK profiles with evaluable plasma APV PK parameter data; thus, the sample sizes were limited. Results are stratified by age cohort and formulation since these factors can impact PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| FPV/RTV | Geometric Mean of Steady State Plasma Amprenavir (APV) Parameter: AUC(0-tau) | 47.3 hours*micrograms/milliliter |
| PI-Experienced | Geometric Mean of Steady State Plasma Amprenavir (APV) Parameter: AUC(0-tau) | 47.6 hours*micrograms/milliliter |
| FPV/RTV 30/6 mg/kg Once Daily (Suspension), 12-18 Years | Geometric Mean of Steady State Plasma Amprenavir (APV) Parameter: AUC(0-tau) | 75.5 hours*micrograms/milliliter |
| FPV/RTV 1400/200 mg Once Daily (Tablet), 12-18 Years | Geometric Mean of Steady State Plasma Amprenavir (APV) Parameter: AUC(0-tau) | 71.8 hours*micrograms/milliliter |
Primary
Geometric Mean of Steady State Plasma APV Parameter: CL/F
Geometric mean is a type of average that indicates the central tendency of a set of values and is calculated by multiplying all the numbers in a set, and then taking the nth root of the resulting product. CL/F=apparent plasma clearance.
Time frame: 0, 1, 2, 4, 8, 12, and 24 hours post dosing at Week 4
Population: The PK Parameter Population included all participants who underwent plasma PK sampling and provided full PK profiles with evaluable plasma APV PK parameter data; thus, the sample sizes were limited. Results are stratified by age cohort and formulation since these factors can impact PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| FPV/RTV | Geometric Mean of Steady State Plasma APV Parameter: CL/F | 278 milliliters/minute |
Primary
Geometric Mean of Steady State Plasma APV Parameter: CL/F
Geometric mean is a type of average that indicates the central tendency of a set of values and is calculated by multiplying all the numbers in a set, and then taking the nth root of the resulting product. CL/F=apparent plasma clearance.
Time frame: 0, 1, 2, 4, 8, 12, and 24 hours post dosing at Week 4
Population: The PK Parameter Population included all participants who underwent plasma PK sampling and provided full PK profiles with evaluable plasma APV PK parameter data; thus, the sample sizes were limited. Results are stratified by age cohort and formulation since these factors can impact PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| FPV/RTV | Geometric Mean of Steady State Plasma APV Parameter: CL/F | 10.5 milliliters/minute/kilogram |
| PI-Experienced | Geometric Mean of Steady State Plasma APV Parameter: CL/F | 10.6 milliliters/minute/kilogram |
| FPV/RTV 30/6 mg/kg Once Daily (Suspension), 12-18 Years | Geometric Mean of Steady State Plasma APV Parameter: CL/F | 6.57 milliliters/minute/kilogram |
| FPV/RTV 1400/200 mg Once Daily (Tablet), 12-18 Years | Geometric Mean of Steady State Plasma APV Parameter: CL/F | 4.95 milliliters/minute/kilogram |
Primary
Geometric Mean of Steady State Plasma APV Parameter: Cmax
Geometric mean is a type of average that indicates the central tendency of a set of values and is calculated by multiplying all the numbers in a set, and then taking the nth root of the resulting product. Cmax= concentration maximum.
Time frame: 0, 1, 2, 4, 8, 12, and 24 hours post dosing at Week 4
Population: The PK Parameter Population included all participants who underwent plasma PK sampling and provided full PK profiles with evaluable plasma APV PK parameter data; thus, the sample sizes were limited. Results are stratified by age cohort and formulation since these factors can impact PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| FPV/RTV | Geometric Mean of Steady State Plasma APV Parameter: Cmax | 4.97 micrograms/milliliter |
| PI-Experienced | Geometric Mean of Steady State Plasma APV Parameter: Cmax | 5.07 micrograms/milliliter |
| FPV/RTV 30/6 mg/kg Once Daily (Suspension), 12-18 Years | Geometric Mean of Steady State Plasma APV Parameter: Cmax | 6.88 micrograms/milliliter |
| FPV/RTV 1400/200 mg Once Daily (Tablet), 12-18 Years | Geometric Mean of Steady State Plasma APV Parameter: Cmax | 7.70 micrograms/milliliter |
Primary
Geometric Mean of Steady State Plasma APV Parameter: t1/2
Geometric mean is a type of average that indicates the central tendency of a set of values and is calculated by multiplying all the numbers in a set, and then taking the nth root of the resulting product. t1/2=elimination half-life. t1/2=elimination half-life.
Time frame: 0, 1, 2, 4, 8, 12, and 24 hours post dosing at Week 4
Population: The PK Parameter Population included all participants who underwent plasma PK sampling and provided full PK profiles with evaluable plasma APV PK parameter data; thus, the sample sizes were limited. Results are stratified by age cohort and formulation since these factors can impact PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| FPV/RTV | Geometric Mean of Steady State Plasma APV Parameter: t1/2 | 17.5 hours |
| PI-Experienced | Geometric Mean of Steady State Plasma APV Parameter: t1/2 | 13.6 hours |
| FPV/RTV 30/6 mg/kg Once Daily (Suspension), 12-18 Years | Geometric Mean of Steady State Plasma APV Parameter: t1/2 | 15.0 hours |
| FPV/RTV 1400/200 mg Once Daily (Tablet), 12-18 Years | Geometric Mean of Steady State Plasma APV Parameter: t1/2 | 14.9 hours |
Primary
Least Squares Mean of Plasma APV Parameter: AUC0-tau
A blood sample was drawn on Week 4 over 24 hours (at 0, 1, 2, 4, 8, 12, and 24 hours post dosing). Ratio of geometric least squares mean (90% CI) are presented. Ctau=trough concentration. PK Parameters for QD and BID are compared with Historical adult data. Least squares mean (LSM) are the group means after having controlled for a covariate (i.e., holding it constant at some typical value of the covariate, such as its mean value). LSM is calculated by taking the average of the means within a treatment.
Time frame: 0, 1, 2, 4, 8, 12, and 24 hours post dosing at Week 4
Population: The PK Parameter Population included all participants who underwent plasma PK sampling and provided full PK profiles with evaluable plasma APV PK parameter data; thus, the sample sizes were limited. Results are stratified by age cohort and formulation since these factors can impact PK profiles.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| FPV/RTV | Least Squares Mean of Plasma APV Parameter: AUC0-tau | 0.695 hours*micrograms/milliliters |
| PI-Experienced | Least Squares Mean of Plasma APV Parameter: AUC0-tau | 0.699 hours*micrograms/milliliters |
| FPV/RTV 30/6 mg/kg Once Daily (Suspension), 12-18 Years | Least Squares Mean of Plasma APV Parameter: AUC0-tau | 1.11 hours*micrograms/milliliters |
| FPV/RTV 1400/200 mg Once Daily (Tablet), 12-18 Years | Least Squares Mean of Plasma APV Parameter: AUC0-tau | 1.06 hours*micrograms/milliliters |
Primary
Least Squares Mean of Plasma APV Parameter: Cmax
A blood sample was drawn on Week 4 over 24 hours (at 0, 1, 2, 4, 8, 12, and 24 hours post dosing). Ratio of geometric least squares mean (90% CI) are presented. Ctau=trough concentration. PK Parameters for QD and BID are compared with Historical adult data. Least squares mean (LSM) are the group means after having controlled for a covariate (i.e., holding it constant at some typical value of the covariate, such as its mean value). LSM is calculated by taking the average of the means within a treatment.
Time frame: 0, 1, 2, 4, 8, 12, and 24 hours post dosing at Week 4.
Population: The PK Parameter Population included all participants who underwent plasma PK sampling and provided full PK profiles with evaluable plasma APV PK parameter data; thus, the sample sizes were limited. Results are stratified by age cohort and formulation since these factors can impact PK profiles.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| FPV/RTV | Least Squares Mean of Plasma APV Parameter: Cmax | 0.663 micrograms/milliliters |
| PI-Experienced | Least Squares Mean of Plasma APV Parameter: Cmax | 0.676 micrograms/milliliters |
| FPV/RTV 30/6 mg/kg Once Daily (Suspension), 12-18 Years | Least Squares Mean of Plasma APV Parameter: Cmax | 0.917 micrograms/milliliters |
| FPV/RTV 1400/200 mg Once Daily (Tablet), 12-18 Years | Least Squares Mean of Plasma APV Parameter: Cmax | 1.03 micrograms/milliliters |
Primary
Least Squares Mean of Plasma APV Parameter: Ctau
A blood sample was drawn on Week 4 over 24 hours (at 0, 1, 2, 4, 8, 12, and 24 hours post dosing). Ratio of geometric least squares mean (90% CI) are presented. Ctau=trough concentration. PK Parameters for QD and BID are compared with Historical adult data. Least squares mean (LSM) are the group means after having controlled for a covariate (i.e., holding it constant at some typical value of the covariate, such as its mean value). LSM is calculated by taking the average of the means within a treatment.
Time frame: 0, 1, 2, 4, 8, 12, and 24 hours post dosing at Week 4.
Population: The PK Parameter Population included all participants who underwent plasma PK sampling and provided full PK profiles with evaluable plasma APV PK parameter data; thus, the sample sizes were limited. Results are stratified by age cohort and formulation since these factors can impact PK profiles.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| FPV/RTV | Least Squares Mean of Plasma APV Parameter: Ctau | 0.716 microgram per milliliter |
| PI-Experienced | Least Squares Mean of Plasma APV Parameter: Ctau | 0.837 microgram per milliliter |
| FPV/RTV 30/6 mg/kg Once Daily (Suspension), 12-18 Years | Least Squares Mean of Plasma APV Parameter: Ctau | 0.963 microgram per milliliter |
| FPV/RTV 1400/200 mg Once Daily (Tablet), 12-18 Years | Least Squares Mean of Plasma APV Parameter: Ctau | 0.706 microgram per milliliter |
Primary
Median Steady State Plasma APV Tmax
tmax: time after administration of the drug when maximum concentration is reached
Time frame: 0, 1, 2, 4, 8, 12, and 24 hours post dosing at Week 4
Population: The PK Parameter Population included all participants who underwent plasma PK sampling and provided full PK profiles with evaluable plasma APV PK parameter data; thus, the sample sizes were limited. Results are stratified by age cohort and formulation since these factors can impact PK profiles.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| FPV/RTV | Median Steady State Plasma APV Tmax | 1.04 hours |
| PI-Experienced | Median Steady State Plasma APV Tmax | 1.12 hours |
| FPV/RTV 30/6 mg/kg Once Daily (Suspension), 12-18 Years | Median Steady State Plasma APV Tmax | 1.08 hours |
| FPV/RTV 1400/200 mg Once Daily (Tablet), 12-18 Years | Median Steady State Plasma APV Tmax | 3.78 hours |
Primary
Number of Participants Who Discontinued Treatment Due to Adverse Events
The number of participants who prematurely discontinued study drug due to adverse events was tabulated. Data are summarized by individual adverse event.
Time frame: Baseline through end of study (at least Week 168)
Population: Safety Population: all participants with documented evidence of having received at least one dose of study drug
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FPV/RTV | Number of Participants Who Discontinued Treatment Due to Adverse Events | Stomach discomfort | 1 Participants |
| FPV/RTV | Number of Participants Who Discontinued Treatment Due to Adverse Events | Any event | 12 Participants |
| FPV/RTV | Number of Participants Who Discontinued Treatment Due to Adverse Events | Nausea | 3 Participants |
| FPV/RTV | Number of Participants Who Discontinued Treatment Due to Adverse Events | Vomiting | 3 Participants |
| FPV/RTV | Number of Participants Who Discontinued Treatment Due to Adverse Events | Hyperglycaemia | 1 Participants |
| FPV/RTV | Number of Participants Who Discontinued Treatment Due to Adverse Events | Hypertriglyceridaemia | 1 Participants |
| FPV/RTV | Number of Participants Who Discontinued Treatment Due to Adverse Events | Blood alkaline phosphatase increased | 1 Participants |
| FPV/RTV | Number of Participants Who Discontinued Treatment Due to Adverse Events | Hodgkin's disease | 1 Participants |
| FPV/RTV | Number of Participants Who Discontinued Treatment Due to Adverse Events | Haemoptysis | 1 Participants |
Primary
Number of Participants With Any Drug-related Grade 2 to 4 Adverse Event
The number of participants with drug-related adverse events coded as Grade 2 (mild), Grade 3 (severe), or Grade 4 (life-threatening).
Time frame: Baseline through end of study (at least Week 168)
Population: Safety Population: all participants with documented evidence of having received at least one dose of study drug
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FPV/RTV | Number of Participants With Any Drug-related Grade 2 to 4 Adverse Event | All Grade 2-4 events | 7 Participants |
| FPV/RTV | Number of Participants With Any Drug-related Grade 2 to 4 Adverse Event | Vomiting | 0 Participants |
| FPV/RTV | Number of Participants With Any Drug-related Grade 2 to 4 Adverse Event | Diarrhea | 2 Participants |
| FPV/RTV | Number of Participants With Any Drug-related Grade 2 to 4 Adverse Event | Nausea | 2 Participants |
| FPV/RTV | Number of Participants With Any Drug-related Grade 2 to 4 Adverse Event | Blood alkaline phosphatase increased | 1 Participants |
| FPV/RTV | Number of Participants With Any Drug-related Grade 2 to 4 Adverse Event | Blood triglycerides increased | 1 Participants |
| FPV/RTV | Number of Participants With Any Drug-related Grade 2 to 4 Adverse Event | Abdominal pain | 0 Participants |
| FPV/RTV | Number of Participants With Any Drug-related Grade 2 to 4 Adverse Event | Benign salivary gland neoplasm | 0 Participants |
| FPV/RTV | Number of Participants With Any Drug-related Grade 2 to 4 Adverse Event | Blood cholesterol increased | 1 Participants |
| FPV/RTV | Number of Participants With Any Drug-related Grade 2 to 4 Adverse Event | Eosinophil count increased | 0 Participants |
| FPV/RTV | Number of Participants With Any Drug-related Grade 2 to 4 Adverse Event | Hemoptysis | 0 Participants |
| FPV/RTV | Number of Participants With Any Drug-related Grade 2 to 4 Adverse Event | Hyperglycemia | 0 Participants |
| FPV/RTV | Number of Participants With Any Drug-related Grade 2 to 4 Adverse Event | Hypertrichosis | 0 Participants |
| FPV/RTV | Number of Participants With Any Drug-related Grade 2 to 4 Adverse Event | Lipodystrophy acquired | 1 Participants |
| FPV/RTV | Number of Participants With Any Drug-related Grade 2 to 4 Adverse Event | Lipohypertrophy | 0 Participants |
| FPV/RTV | Number of Participants With Any Drug-related Grade 2 to 4 Adverse Event | Rash | 0 Participants |
| FPV/RTV | Number of Participants With Any Drug-related Grade 2 to 4 Adverse Event | Somnolence | 1 Participants |
| FPV/RTV | Number of Participants With Any Drug-related Grade 2 to 4 Adverse Event | Stomach discomfort | 1 Participants |
| PI-Experienced | Number of Participants With Any Drug-related Grade 2 to 4 Adverse Event | Lipodystrophy acquired | 0 Participants |
| PI-Experienced | Number of Participants With Any Drug-related Grade 2 to 4 Adverse Event | All Grade 2-4 events | 14 Participants |
| PI-Experienced | Number of Participants With Any Drug-related Grade 2 to 4 Adverse Event | Eosinophil count increased | 1 Participants |
| PI-Experienced | Number of Participants With Any Drug-related Grade 2 to 4 Adverse Event | Vomiting | 5 Participants |
| PI-Experienced | Number of Participants With Any Drug-related Grade 2 to 4 Adverse Event | Stomach discomfort | 0 Participants |
| PI-Experienced | Number of Participants With Any Drug-related Grade 2 to 4 Adverse Event | Diarrhea | 1 Participants |
| PI-Experienced | Number of Participants With Any Drug-related Grade 2 to 4 Adverse Event | Hemoptysis | 1 Participants |
| PI-Experienced | Number of Participants With Any Drug-related Grade 2 to 4 Adverse Event | Nausea | 1 Participants |
| PI-Experienced | Number of Participants With Any Drug-related Grade 2 to 4 Adverse Event | Lipohypertrophy | 1 Participants |
| PI-Experienced | Number of Participants With Any Drug-related Grade 2 to 4 Adverse Event | Blood alkaline phosphatase increased | 1 Participants |
| PI-Experienced | Number of Participants With Any Drug-related Grade 2 to 4 Adverse Event | Hyperglycemia | 1 Participants |
| PI-Experienced | Number of Participants With Any Drug-related Grade 2 to 4 Adverse Event | Blood triglycerides increased | 0 Participants |
| PI-Experienced | Number of Participants With Any Drug-related Grade 2 to 4 Adverse Event | Somnolence | 0 Participants |
| PI-Experienced | Number of Participants With Any Drug-related Grade 2 to 4 Adverse Event | Abdominal pain | 1 Participants |
| PI-Experienced | Number of Participants With Any Drug-related Grade 2 to 4 Adverse Event | Hypertrichosis | 1 Participants |
| PI-Experienced | Number of Participants With Any Drug-related Grade 2 to 4 Adverse Event | Benign salivary gland neoplasm | 1 Participants |
| PI-Experienced | Number of Participants With Any Drug-related Grade 2 to 4 Adverse Event | Rash | 1 Participants |
| PI-Experienced | Number of Participants With Any Drug-related Grade 2 to 4 Adverse Event | Blood cholesterol increased | 0 Participants |
Primary
Number of Participants With Grade 3 or 4 Treatment-emergent Laboratory Abnormalities
The number of participants with Grade 3 (severe) or Grade 4 (life-threatening) laboratory abnormalities while on study treatment.
Time frame: Baseline through end of study (at least Week 168)
Population: Safety Population: all participants with documented evidence of having received at least one dose of study drug
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FPV/RTV | Number of Participants With Grade 3 or 4 Treatment-emergent Laboratory Abnormalities | All parameters | 6 Participants |
| FPV/RTV | Number of Participants With Grade 3 or 4 Treatment-emergent Laboratory Abnormalities | Alanine aminotransferase | 2 Participants |
| FPV/RTV | Number of Participants With Grade 3 or 4 Treatment-emergent Laboratory Abnormalities | Aspartate aminotransferase | 3 Participants |
| FPV/RTV | Number of Participants With Grade 3 or 4 Treatment-emergent Laboratory Abnormalities | Cholesterol | 0 Participants |
| FPV/RTV | Number of Participants With Grade 3 or 4 Treatment-emergent Laboratory Abnormalities | Hyperglycemia | 0 Participants |
| FPV/RTV | Number of Participants With Grade 3 or 4 Treatment-emergent Laboratory Abnormalities | Hypoglycemia | 0 Participants |
| FPV/RTV | Number of Participants With Grade 3 or 4 Treatment-emergent Laboratory Abnormalities | Serum lipase | 0 Participants |
| FPV/RTV | Number of Participants With Grade 3 or 4 Treatment-emergent Laboratory Abnormalities | Triglycerides | 1 Participants |
| FPV/RTV | Number of Participants With Grade 3 or 4 Treatment-emergent Laboratory Abnormalities | Leucopenia | 1 Participants |
| FPV/RTV | Number of Participants With Grade 3 or 4 Treatment-emergent Laboratory Abnormalities | Neutropenia | 12 Participants |
| FPV/RTV | Number of Participants With Grade 3 or 4 Treatment-emergent Laboratory Abnormalities | Thrombocytopenia | 2 Participants |
| FPV/RTV | Number of Participants With Grade 3 or 4 Treatment-emergent Laboratory Abnormalities | Anemia | 1 Participants |
Secondary
Median Change From Baseline HIV-1 RNA Values at Weeks 12, 48, 96, and 168 Visits
A blood sample was drawn to determine the amount of HIV-1 RNA virus in copies/mL at Weeks 12, 24, 48, 96, and 168. Change from Baseline was defined as the HIV-1 RNA level at Weeks 12, 24, 48, 96, and 168 minus the HIV-1 RNA level at Baseline.
Time frame: Baseline and Weeks 12, 48, 96, and 168
Population: ITT-E Population. Results are stratified by previous PI experience. Participants with previous PI experience may respond differently to FPV.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| FPV/RTV | Median Change From Baseline HIV-1 RNA Values at Weeks 12, 48, 96, and 168 Visits | Week 12 | -2.85 log10 copies/mL |
| FPV/RTV | Median Change From Baseline HIV-1 RNA Values at Weeks 12, 48, 96, and 168 Visits | Week 48 | -2.65 log10 copies/mL |
| FPV/RTV | Median Change From Baseline HIV-1 RNA Values at Weeks 12, 48, 96, and 168 Visits | Week 96 | -2.52 log10 copies/mL |
| FPV/RTV | Median Change From Baseline HIV-1 RNA Values at Weeks 12, 48, 96, and 168 Visits | Week 168 | -2.88 log10 copies/mL |
| PI-Experienced | Median Change From Baseline HIV-1 RNA Values at Weeks 12, 48, 96, and 168 Visits | Week 168 | -2.39 log10 copies/mL |
| PI-Experienced | Median Change From Baseline HIV-1 RNA Values at Weeks 12, 48, 96, and 168 Visits | Week 12 | -2.03 log10 copies/mL |
| PI-Experienced | Median Change From Baseline HIV-1 RNA Values at Weeks 12, 48, 96, and 168 Visits | Week 96 | -1.76 log10 copies/mL |
| PI-Experienced | Median Change From Baseline HIV-1 RNA Values at Weeks 12, 48, 96, and 168 Visits | Week 48 | -1.65 log10 copies/mL |
Secondary
Median Change From Baseline in CD4+ Values at Week 12, 48, 96, and 168 Visits
A blood sample was drawn to determine the CD4+ cell count at Weeks 24, 48, 96, and 168. Change from Baseline was defined as the CD4+ cell count at Weeks 24, 48, 96, and 168 minus the CD4+ cell count at Baseline.
Time frame: Baseline and Weeks 12, 48, 96, and 168
Population: ITT-E Population. Results are stratified by previous PI experience. Participants with previous PI experience may respond differently to FPV.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| FPV/RTV | Median Change From Baseline in CD4+ Values at Week 12, 48, 96, and 168 Visits | Week 12 | 95 Cells/mm3 |
| FPV/RTV | Median Change From Baseline in CD4+ Values at Week 12, 48, 96, and 168 Visits | Week 48 | 150 Cells/mm3 |
| FPV/RTV | Median Change From Baseline in CD4+ Values at Week 12, 48, 96, and 168 Visits | Week 96 | 160 Cells/mm3 |
| FPV/RTV | Median Change From Baseline in CD4+ Values at Week 12, 48, 96, and 168 Visits | Week 168 | 180 Cells/mm3 |
| PI-Experienced | Median Change From Baseline in CD4+ Values at Week 12, 48, 96, and 168 Visits | Week 168 | 0 Cells/mm3 |
| PI-Experienced | Median Change From Baseline in CD4+ Values at Week 12, 48, 96, and 168 Visits | Week 12 | 40 Cells/mm3 |
| PI-Experienced | Median Change From Baseline in CD4+ Values at Week 12, 48, 96, and 168 Visits | Week 96 | 40 Cells/mm3 |
| PI-Experienced | Median Change From Baseline in CD4+ Values at Week 12, 48, 96, and 168 Visits | Week 48 | 120 Cells/mm3 |
Secondary
Number of Participants With APV Resistance Associated HIV-1 RNA Genotypic Mutations and Phenotypic Resistance at Time of Virologic Failure Not Present at Baseline
A blood sample was drawn for participants failing to respond to therapy, and the mutations present in the virus were identified. For each participant, the mutations found at the time of failure were compared with any mutations found in the blood sample at baseline. New mutations that developed at the time of virologic failure were tabulated by drug class. Virologic failure is defined as HIV-1 RNA greater than or equal to 400 copies/mL.
Time frame: Time of virologic failure
Population: Participants in the ITT-E Population who met the virologic failure definition. Results are stratified by previous PI experience. Participants with previous PI experience may respond differently to FPV.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FPV/RTV | Number of Participants With APV Resistance Associated HIV-1 RNA Genotypic Mutations and Phenotypic Resistance at Time of Virologic Failure Not Present at Baseline | 2 Participants |
| PI-Experienced | Number of Participants With APV Resistance Associated HIV-1 RNA Genotypic Mutations and Phenotypic Resistance at Time of Virologic Failure Not Present at Baseline | 2 Participants |
Secondary
Percentage of Participants With HIV-1 RNA <400 Copies Per mL at Weeks 12, 48, 96, and 168 (Time to Loss of Virologic Response [TLOVR] Analysis)
A blood sample was drawn to determine the amount of HIV-1 RNA virus in copies per milliliter (mL) at Weeks 12, 48, 96, and 196. The percentage of participants with HIV-1 RNA \<400 copies/mL at Weeks 12, 48, 96, 168 was determined by the TLOVR algorithm with stratification by the six randomization strata. TLOVR analysis categorizes participants by treatment response. Responders were participants with confirmed viral load \<400copies/mL on two consecutive visits.
Time frame: Weeks 12, 48, 96, and 168
Population: The Intent-to-Treat Exposed (ITT \[E\]) Population consisted of all subjects with documented evidence of having received at least one dose of study drug. Results are stratified by previous protease inhibitor (PI) experience. Participants with previous PI experience may respond differently to FPV.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FPV/RTV | Percentage of Participants With HIV-1 RNA <400 Copies Per mL at Weeks 12, 48, 96, and 168 (Time to Loss of Virologic Response [TLOVR] Analysis) | Week 12 | 22 percentage of participants |
| FPV/RTV | Percentage of Participants With HIV-1 RNA <400 Copies Per mL at Weeks 12, 48, 96, and 168 (Time to Loss of Virologic Response [TLOVR] Analysis) | Week 48 | 16 percentage of participants |
| FPV/RTV | Percentage of Participants With HIV-1 RNA <400 Copies Per mL at Weeks 12, 48, 96, and 168 (Time to Loss of Virologic Response [TLOVR] Analysis) | Week 96 | 13 percentage of participants |
| FPV/RTV | Percentage of Participants With HIV-1 RNA <400 Copies Per mL at Weeks 12, 48, 96, and 168 (Time to Loss of Virologic Response [TLOVR] Analysis) | Week 168 | 11 percentage of participants |
| PI-Experienced | Percentage of Participants With HIV-1 RNA <400 Copies Per mL at Weeks 12, 48, 96, and 168 (Time to Loss of Virologic Response [TLOVR] Analysis) | Week 168 | 7 percentage of participants |
| PI-Experienced | Percentage of Participants With HIV-1 RNA <400 Copies Per mL at Weeks 12, 48, 96, and 168 (Time to Loss of Virologic Response [TLOVR] Analysis) | Week 12 | 20 percentage of participants |
| PI-Experienced | Percentage of Participants With HIV-1 RNA <400 Copies Per mL at Weeks 12, 48, 96, and 168 (Time to Loss of Virologic Response [TLOVR] Analysis) | Week 96 | 11 percentage of participants |
| PI-Experienced | Percentage of Participants With HIV-1 RNA <400 Copies Per mL at Weeks 12, 48, 96, and 168 (Time to Loss of Virologic Response [TLOVR] Analysis) | Week 48 | 16 percentage of participants |