Clinical trial NCT00071760: Study Of An Investigational Regimen Including FDA Approved HIV Drugs In HIV-Infected Pediatric Subjects
Official title: A 48 Week, Phase II, Open-label, 2-cohort, Multicenter Study to Evaluate the Pharmacokinetics, Safety, Tolerability and Antiviral Activity of GW433908 and GW433908/RTV When Administered to HIV-1 Infected Protease Inhibitor (PI) Naive and PI-experienced Pediatric Subjects Aged 4 Weeks to <2 Years.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Infection, Human Immunodeficiency Virus
HIV Infections
Keywords: pediatrics
ritonavir
amprenavir
AGENERASE
HIV
Lexiva
protease inhibitors
HIV Infection
fosamprenavir
Lead sponsor: ViiV Healthcare
Sponsor class: INDUSTRY
Collaborators: name: GlaxoSmithKline
First posted: 2003-10-31
Enrollment: 59
Sex: ALL
Minimum age (years): 4
Maximum age (years): 2
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a 48-week study to evaluate the safety, tolerability, pharmacokinetics, and antiviral activity of an investigational regimen including FDA approved HIV drugs in HIV-infected pediatric subjects, ages 4 weeks to \< 2 years old.

Detailed description: A 48 week, Phase II, open-label, 2-cohort, multicenter study to evaluate the pharmacokinetics, safety, tolerability and antiviral activity of GW433908 and GW433908/RTV when administered to HIV-1 infected protease inhibitor (PI) naive and PI-experienced pediatric subjects aged 4 weeks to \<2 years.

Eligibility criteria: Inclusion Criteria:

* Male or female 4 weeks to \<2 years of age. Cohort 1 (6 months - \<2 years): Subjects must be \<2 years of age at the Week 2 visit therefore the maximum age at screening is 22 months.

Cohort 2 (4 weeks - \<6 months): Subjects must be \<6 months of age at the Week 2 visit, therefore the maximum age at screening is 4 months for entry into this cohort.

* Parent or legal guardian is willing and able to provide written informed consent for the subject to participate in the trial.
* Screening plasma HIV-1 RNA level \>=400copies/mL.
* Subjects who, in the investigator's opinion, and following viral resistance testing if conducted, are able to construct an active Nucleoside Reverse Transcriptase Inhibitor (NRTI) backbone regimen consisting of 2 NRTIs.
* Subjects must meet one of the following criteria:

Therapy-naïve or PI-naïve subjects (defined as having received less than one week of any PI).

PI-experienced subjects defined as having prior experience with no more than three PIs. Prior RTV-boosted PI therapy will be considered as only one PI as long as the RTV dose was lower than that recommended for use of RTV as an antiretroviral agent.

Exclusion Criteria:

* Prior history of having received APV.
* Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) therapy within 14 days prior to study drug administration (single or multiple dose) or anticipated need for concurrent NNRTI therapy during the study period.
* PI therapy within 5 days prior to study drug administration (applicable only for subjects undergoing single dose visits)
* Subjects and/or parents/legal guardians who, in the investigator's opinion, are not able to comply with the requirements of the study.
* Subject is in the initial acute phase of a Centers for Disease Control and Prevention (CDC) Clinical Category C event or infection (per 1994 classification) at Baseline. Subject may be enrolled provided they are receiving treatment for the infections, such treatment not being contraindicated with FPV, and subjects are clinically improving at the Baseline visit.
* 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, hepatitis, or clinically relevant pancreatitis) which, in the opinion of the investigator, might compromise the safety of the subject.
* Any acute laboratory abnormality at screen which, in the opinion of the investigator, should preclude the subject's participation in the study of an investigational compound. If subjects are found to have an acute Grade 4 laboratory abnormality at screening, this test may be repeated once within the screening window. Any verified Grade 4 laboratory abnormality would exclude a subject from study participation.
* Grade 3 or higher (\>10x ULN) serum aminotransferase levels (alanine aminotransferase, ALT and/or aspartate aminotransferase, 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, diazepam, dihydroergotamine, encainide, ergonovine, ergotamine, estazolam, flecainide, flurazepam, lovastatin, meperidine, methylergonovine, midazolam, pimozide, piroxicam, propafenone, propoxyphene, quinidine, simvastatin, terfenadine, and triazolam (these drugs have been excluded for safety reasons).

Carbamazepine, dexamethasone, phenobarbital, primidone, rifampin, St Johns Wort, (these drugs have been excluded because they have the potential to decrease plasma protease inhibitor concentrations).

* Treatment with other investigational drugs/therapies within 28 days prior to receiving study medication (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).
* 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).

Primary outcomes:
measure: Plasma Amprenavir (APV) AUC (0-tau[τ])
timeFrame: Week 48
measure: Plasma APV Cmax
timeFrame: Week 48
measure: Plasma APV Cτ
timeFrame: Week 48
measure: Plasma APV CL/F Following Dosing Expressed in mL/Min/kg
timeFrame: Week 48
measure: Plasma APV CL/F Following Dosing Expressed in mL/Min
timeFrame: Week 48
measure: Plasma Unbound APV Cτ
timeFrame: Week 48
measure: Plasma Unbound APV Percent Protein Binding (%Cτ)
timeFrame: Week 48
measure: Absolute Values of Alanine Amino Transferase (ALT) and Aspartate Amino Transferase (AST) at Baseline (Day 1), Weeks 4, 12, 24, 36, and 48
timeFrame: Baseline (Day 1) and Weeks 4, 12, 24, 36, and 48
measure: Absolute Values of Cholesterol, Glucose, High Density Lipoprotein (HDL) Cholesterol, Low Density Lipoprotein (LDL) and Triglyceride (TG) at Baseline (Day 1), Weeks 4, 12, 24, 36, and 48
timeFrame: Baseline (Day 1) and Weeks 4, 12, 24, 36, and 48
measure: Absolute Values of Serum Lipase at Baseline (Day 1), Weeks 4, 12, 24, and 48
timeFrame: Baseline (Day 1) and Weeks 4, 12, 24, and 48
measure: Number of Participants With the Indicated Treatment-emergent (TE) Grade 3/4 Laboratory Abnormalities
timeFrame: Baseline (Day 1) until Week 48
measure: Number of Participants With the Indicated Treatment-emergent (TE) Grade 3/4 Adverse Events (AE)
timeFrame: Baseline (Day 1) until Week 48
measure: Number of Participants Who Permanently Discontinued the Treatment Due to an AE
timeFrame: Baseline (Day 1) until Week 48
Secondary outcomes:
measure: Number of Participants With Plasma Human Immuno Virus Type 1 (HIV-1) Ribonucleic Acid (RNA) Levels < 400 Copies/Milliliter at Each Study Visit
timeFrame: Baseline (Day 1) and up to Week 684
measure: Change From Baseline in Plasma HIV-1 RNA Levels at Each Study Visit
timeFrame: Baseline (Day 1) and up to Week 684
measure: Absolute Values of Cluster of Differentiation 4 (CD4+) Cell Counts by Study Visit
timeFrame: Baseline (Day 1) and up to week 684
measure: Plasma FPV Concentrations
timeFrame: Post -Week 48 through Week 684
measure: Number of Participants With Treatment-Emergent Mutations at Virologic Failure Timepoint
timeFrame: Week 48 to Week 684
measure: Number of Participants With Treatment-Emergent Changes in HIV-1 Phenotypic Drug Susceptibility
timeFrame: Post-Week 48 to Week 684
measure: Number of Participants With Plasma HIV-1 Ribonucleic Acid (RNA) <400 Copies Per Milliliter at Baseline and Weeks 4, 12, 24, 36, and 48 (MSD=F)
timeFrame: Baseline and Weeks 4, 12, 24, 36, and 48
measure: Median Plasma HIV-1 RNA (log10 Copies/mL) at Baseline and Weeks 4, 12, 24, 36, and 48 (Observed Analysis)
timeFrame: Baseline and Weeks 4, 12, 24, 36, and 48
measure: Median Change From Baseline in Plasma HIV-1 RNA (log10 Copies/mL) at Weeks 4, 12, 24, 36, and 48 (Observed Analysis)
timeFrame: Baseline and Weeks 4, 12, 24, 36, and 48
measure: Number of Participants With at Least a 1.0 log10 HIV-1 RNA Decrease From Baseline at Weeks 4, 12, 24, 36, and 48 (MSD=F Analysis)
timeFrame: Baseline and Weeks 4, 12, 24, 36, and 48
measure: Median Percent Cluster of Differentiation Antigen 4 (CD4+) Cell Count at Baseline and at Weeks 4, 12, 24, 36, and 48
timeFrame: Baseline and Weeks 4, 12, 24, 36, and 48
measure: Median Percent Change From Baseline in CD4+ Cell Count at Weeks 4, 12, 24, 36, and 48
timeFrame: Baseline and Weeks 4, 12, 24, 36, and 48
measure: Number of Participants With the Indicated Virological Outcome at Week 48
timeFrame: Week 48
measure: Plasma Ritonavir (RTV) AUC (0-τ)
timeFrame: Week 48
measure: Plasma RTV Cmax
timeFrame: Week 48
measure: Plasma RTV Cτ
timeFrame: Week 48
measure: Plasma RTV CL/F Expressed in mL/Min/kg
timeFrame: Week 48
measure: Plasma RTV CL/F Expressed in mL/Min
timeFrame: Week 48
measure: Number of Confirmed Virologic Failure Participants (Par.) With Treatment-emergent HIV Genotypic Resistance in Reverse Transcriptase and Protease
timeFrame: Baseline through Week 48
measure: Number of Confirmed Virologic Failure Participants (Par.) With Treatment-emergent Reductions in Drug Susceptibility (DS)
timeFrame: Baseline through Week 48
measure: Number of Participants Reporting Perfect Adherence at Weeks 2, 12, 24, and 48 as Assessed by the Study Coordinator Using the Adherence Questionnaire
timeFrame: Weeks 2, 12, 24, and 48
measure: Number of Participants With the Indicated Response Scores for the Parent/Guardian (P/G) Perception of FPV Oral Suspension Questionnaire: Items 1 to 4
timeFrame: Weeks 2, 24, and 48/premature study discontinuation
measure: Number of Participants With the Indicated Response Scores for the Parent/Guardian Perception of the Child's Assessment of FPV Oral Suspension Questionnaire: Items (I) 5 to 10
timeFrame: Weeks (W) 2, 24, and 48/premature study discontinuation
measure: Correlation Between Steady-state Plasma APV PK Parameters to Changes in Plasma HIV-1 RNA Concentrations, CD4+ Percentages, and/or the Occurrence of Adverse Events
timeFrame: Week 48
measure: Plasma FPV AUC (0-τ)
timeFrame: Week 48
measure: Plasma FPV Cmax and Cτ
timeFrame: Week 48
measure: Plasma FPV CL/F Expressed in mL/Min/kg
timeFrame: Week 48
measure: Plasma FPV CL/F Expressed in mL/Min
timeFrame: Week 48
Other outcomes:
measure: Number of Participants With Treatment Emergent Adverse Events (AEs)
timeFrame: Day 1 and up to week 684
measure: Number of Participants With Clinical Chemistry Toxicities
timeFrame: Day 1 and up to Week 684
measure: Number of Participants With Hematology Toxicities
timeFrame: Day 1 and up to Week 684
measure: Number of Participants With Treatment Limiting Toxicities
timeFrame: Day 1 and up to Week 684
measure: Number of Participants Who Permanently Discontinued the Treatment Due to Adverse Event
timeFrame: Day 1 and up to Week 684
Locations:
city: Jacksonville
country: United States
facility: GSK Investigational Site
state: Florida
city: Durham
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Buenos Aires
country: Argentina
facility: GSK Investigational Site
city: Mexico, D.F.
country: Mexico
facility: GSK Investigational Site
city: Mexico
country: Mexico
facility: GSK Investigational Site
city: Almada
country: Portugal
facility: GSK Investigational Site
city: Amadora
country: Portugal
facility: GSK Investigational Site
city: Lisboa
country: Portugal
facility: GSK Investigational Site
city: San Juan
country: Puerto Rico
facility: GSK Investigational Site
city: Moscow
country: Russian Federation
facility: GSK Investigational Site
city: Moscow
country: Russian Federation
facility: GSK Investigational Site
city: St. Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: Durban
country: South Africa
facility: GSK Investigational Site
state: KwaZulu- Natal
city: Parow Valley
country: South Africa
facility: GSK Investigational Site
state: Western Province
city: Soweto
country: South Africa
facility: GSK Investigational Site
Study officials:
affiliation: ViiV Healthcare
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Cotton M, Cassim H, Pavia-Ruz N, Garges HP, Perger T, Ford SL, Wire MB, Givens N, Ross LL, Lou Y, Sievers J, Cheng K. Pharmacokinetics, safety and antiviral activity of fosamprenavir/ritonavir-containing regimens in HIV-infected children aged 4 weeks to 2 years-48-week study data. Pediatr Infect Dis J. 2014 Jan;33(1):57-62. doi: 10.1097/INF.0b013e3182a1123a.