Study Of An Investigational Regimen Including FDA Approved HIV Drugs In HIV-Infected Pediatric Subjects

NCT00071760 | Completed Phase 2 Results DMC

• 1 other identifier: APV20002
• Study Type: interventional
• Target: 59
• Locations: 7 countries
• Sites: 15

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.

Conditions

Infection, Human Immunodeficiency Virus; HIV Infections

Keywords

pediatrics; ritonavir; amprenavir; AGENERASE; HIV; Lexiva; protease inhibitors; HIV Infection; fosamprenavir

Outcome Measures

Primary Outcomes (13)

• Plasma Amprenavir (APV) AUC (0-tau[τ])

  Plasma samples were assayed for APV concentrations using a validated assay. The GlaxoSmithKline (GSK) Department of Clinical Pharmacology Modeling and Simulation conducted pharmacokinetic (PK) analysis of the plasma APV concentration-time data using a model-independent approach. As a measure of total drug exposure, the area under the plasma-concentration-versus-time curve over the dosing interval at steady-state (AUC\[0-τ\]), where "τ" is the length of the dosing interval, was calculated by the linear up/log down trapezoidal method. hours, hr.

  Week 48

• Plasma APV Cmax

  The maximum concentration at steady state (Cmax) was measured.

  Week 48

• Plasma APV Cτ

  The plasma concentration at the end of the dosing interval at steady state (Cτ) was measured.

  Week 48

• Plasma APV CL/F Following Dosing Expressed in mL/Min/kg

  Apparent clearance of drug from plasma following extravascular administration (CL/F) was calculated using the formulation: APV Dose in mg/kg units divided by AUC(0-τ). For FPV, doses were expressed in APV molar equivalents (50 mg of FPV = 43.2 mg of APV). Normalizing CL/F for bodyweight allows for comparison of CL/F across populations.

  Week 48

• Plasma APV CL/F Following Dosing Expressed in mL/Min

  Apparent clearance of drug from plasma following extravascular administration (CL/F) was calculated as dose/AUC(0-τ). For FPV, doses were expressed in APV molar equivalents (50 mg of FPV = 43.2 mg of APV).

  Week 48

• Plasma Unbound APV Cτ

  Participants who are \<2 years old may have reduced protein binding; therefore, plasma unbound APV concentrations were measured to determine dosing recommendations at acceptable dosing volumes. Unbound or "free" APV is the fraction of drug that is not bound to protein. Cτ is the plasma concentration at the end of the dosing interval at steady state.

  Week 48

• Plasma Unbound APV Percent Protein Binding (%Cτ)

  Participants who are \<2 years old may have reduced protein binding; therefore, plasma unbound APV concentrations were measured to determine dosing recommendations at acceptable dosing volumes. APV %Cτ unbound is the percentage of the total APV Cτ that is unbound.

  Week 48

• Absolute Values of Alanine Amino Transferase (ALT) and Aspartate Amino Transferase (AST) at Baseline (Day 1), Weeks 4, 12, 24, 36, and 48

  Blood samples of the participants were collected for the evaluation of ALT and AST. Clinical chemistry analyses were carried out using the observed analysis strategy.

  Baseline (Day 1) and Weeks 4, 12, 24, 36, and 48

• 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

  Blood samples of all participants were generally collected under non-fasting conditions (given the age of participants) for the evaluation of cholesterol, serum glucose, HDL cholesterol, LDL cholesterol and triglyceride (TG). Clinical chemistry analyses were carried out using the observed analysis strategy.

  Baseline (Day 1) and Weeks 4, 12, 24, 36, and 48

• Absolute Values of Serum Lipase at Baseline (Day 1), Weeks 4, 12, 24, and 48

  Blood samples of all participants were collected for the evaluation of serum lipase. Clinical chemistry analyses were carried out using the observed analysis strategy. Change from Baseline in serum lipase was calculated as the value at the indicated time point minus the value at Baseline.

  Baseline (Day 1) and Weeks 4, 12, 24, and 48

• Number of Participants With the Indicated Treatment-emergent (TE) Grade 3/4 Laboratory Abnormalities

  TE toxicities were presented for each laboratory parameter. A toxicity was considered TE if it was greater than the Baseline grade, and if it was observed on/after the date of the first dose of study drug (SD), and on/before the date of the last dose of SD. Per the Division of AIDS Table for Grading the Severity of Adult and Pediatric AEs, Grade 3=severe; Grade 4=potentially life-threatening.

  Baseline (Day 1) until Week 48

• Number of Participants With the Indicated Treatment-emergent (TE) Grade 3/4 Adverse Events (AE)

  An AE is any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE is considered TE if it has an onset date on or after the date of the first dose of study drug, and on or before the date of the final dose of study drug. As per the Division of AIDS Table for Grading the Severity of Adult and Pediatric AEs, Grade 3=severe; Grade 4=potentially life-threatening.

  Baseline (Day 1) until Week 48

• Number of Participants Who Permanently Discontinued the Treatment Due to an AE

  An AE is any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

  Baseline (Day 1) until Week 48

Secondary Outcomes (28)

• Number of Participants With Plasma Human Immuno Virus Type 1 (HIV-1) Ribonucleic Acid (RNA) Levels < 400 Copies/Milliliter at Each Study Visit

  Baseline (Day 1) and up to Week 684

• Change From Baseline in Plasma HIV-1 RNA Levels at Each Study Visit

  Baseline (Day 1) and up to Week 684

• Absolute Values of Cluster of Differentiation 4 (CD4+) Cell Counts by Study Visit

  Baseline (Day 1) and up to week 684

• Plasma FPV Concentrations

  Post -Week 48 through Week 684

• Number of Participants With Treatment-Emergent Mutations at Virologic Failure Timepoint

  Week 48 to Week 684

Other Outcomes (5)

• Number of Participants With Treatment Emergent Adverse Events (AEs)

  Day 1 and up to week 684

• Number of Participants With Clinical Chemistry Toxicities

  Day 1 and up to Week 684

• Number of Participants With Hematology Toxicities

  Day 1 and up to Week 684

Study Arms (2)

Arm A - 4weeks - less than 2 years old (FPV/RTV bid)

EXPERIMENTAL

Cohort 2A - 4weeks - less than 6 months old. Fosamprenavir (FPV) 50 mg/mL oral suspension/ritonavir (RTV) 80 mg/mL oral solution twice daily (BID) Cohort 1A - 6 months - less than 2yrs old. Fosamprenavir (FPV) 50 mg/mL oral suspension/ritonavir (RTV) 80 mg/mL oral solution twice daily (BID)

Drug: GW433908; Drug: ritonavir

Arm B- 4weeks - less than 2 years old (FPV bid)

EXPERIMENTAL

Cohort 2B - 4weeks - less than 6 months old. Fosamprenavir (FPV) 50 mg/mL oral suspension twice daily (BID) Cohort 1B - 6 months - less than 2yrs old. Fosamprenavir (FPV) 50 mg/mL oral suspension twice daily (BID)

Drug: GW433908

Interventions

GW433908 DRUG

Fosamprenavir suspension bid

Arm A - 4weeks - less than 2 years old (FPV/RTV bid); Arm B- 4weeks - less than 2 years old (FPV bid)

ritonavir DRUG

Ritonavir solution bid

Also known as: GW433908

Arm A - 4weeks - less than 2 years old (FPV/RTV bid)

Eligibility Criteria

• Age: 4 Weeks - 2 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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.

You may not qualify if:

• 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).

Sponsors & Collaborators

• ViiV Healthcare: lead
• GlaxoSmithKline: collaborator

Study Sites (15)

GSK Investigational Site

Jacksonville, Florida, 32209, United States

Location

GSK Investigational Site

Durham, North Carolina, 27705, United States

Location

GSK Investigational Site

Buenos Aires, 1405, Argentina

Location

GSK Investigational Site

Mexico City, 06720, Mexico

Location

GSK Investigational Site

México, 6720, Mexico

Location

GSK Investigational Site

Almada, 2805-267, Portugal

Location

GSK Investigational Site

Amadora, 2700, Portugal

Location

GSK Investigational Site

Lisbon, 1649-035, Portugal

Location

GSK Investigational Site

San Juan, 00935, Puerto Rico

Location

GSK Investigational Site

Moscow, 105275, Russia

Location

GSK Investigational Site

Moscow, 129110, Russia

Location

GSK Investigational Site

Saint Petersburg, 196645, Russia

Location

GSK Investigational Site

Durban, KwaZulu-Natal, 4013, South Africa

Location

GSK Investigational Site

Parow Valley, Western Province, 7505, South Africa

Location

GSK Investigational Site

Soweto, 2013, South Africa

Location

Related Publications (1)

• 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.

  PMID: 23811743 BACKGROUND

MeSH Terms

Conditions

Infections; Acquired Immunodeficiency Syndrome; HIV Infections

Interventions

fosamprenavir; Ritonavir

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Slow Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: GSK Response Center
• Organization: ViiV Healthcare

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  ViiV Healthcare

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 30, 2003
• First Posted: October 31, 2003
• Study Start: October 23, 2003
• Primary Completion: July 5, 2011
• Study Completion: March 29, 2022
• Last Updated: October 10, 2023
• Results First Posted: August 23, 2012

Record last verified: 2023-10

Locations

AR (1); PR (1); ME (2); PT (3); US (2); RU (3); ZA (3)