48-Week Study Of GW433908 And Ritonavir Or GW433908 Alone, Twice Daily In Pediatric Patients With HIV Infection

NCT00089583 | Completed Phase 2 Results DMC

• 1 other identifier: APV29005
• Study Type: interventional
• Target: 110
• Locations: 7 countries
• Sites: 39

Brief Summary

This is a 48-week study to collect information on the safety and activity of an investigational medicine in patients, ages 2 to 18 years old, with HIV infection .

Conditions

Infection, Human Immunodeficiency Virus I

Keywords

antiretroviral therapy; pediatrics; AGENERASE; amprenavir; fosamprenavir; HIV Infection; ritonavir; protease inhibitor; LEXIVA

Outcome Measures

Primary Outcomes (12)

• 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. hr, hour; µg, micrograms; mL, milliliter.

  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 mg/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 mg

  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 APV Tmax

  The time to reach the maximum concentration (Cmax) at steady state is defined as tmax.

  Week 48

• Plasma APV t1/2

  The apparent terminal phase half-life (t1/2) is calculated as loge2/λz. The apparent terminal phase rate constant (λz) is the slope of the terminal portion of the logarithmically transformed concentration-time data as estimated by linear regression.

  Week 48

• Number of Participants Who Permanently Discontinued the Treatment Due to Any Adverse Event (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.

  Week 48

• Change From Baseline in Triglycerides, Total Cholesterol, Low-density Lipoprotein (LDL) Cholesterol, High-density Lipoprotein (HDL) Cholesterol, and Serum Glucose at Week 48

  Blood samples of all participants were collected under fasting conditions for the evaluation of triglycerides, total cholesterol, HDL cholesterol, LDL cholesterol, and serum glucose. Clinical chemistry analyses were carried out using the observed analysis strategy. Change from Baseline in triglycerides, total cholesterol, HDL cholesterol, LDL cholesterol, and serum glucose was calculated as the value at Week 48 minus the value at Baseline.

  Baseline (Day 1) and Week 48

• Change From Baseline in Serum Lipase at Week 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 Week 48 minus the value at Baseline.

  Baseline (Day 1) and Week 48

• Change From Baseline in Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) at Week 48

  Blood samples of the participants were collected for the evaluation of AST and ALT. Clinical chemistry analyses were carried out using the observed analysis strategy. Change from Baseline in AST and ALT was calculated as the value at Week 48 minus the value at Baseline.

  Baseline (Day 1) and Week 48

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

  A toxicity was considered TE if it was \> 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. Leucopenia is the decrease in the number of leucocytes (white blood cells \[WBCs\]); neutropenia is the decrease in the number of neutrophils (type of WBCs). Per the Division of AIDS Table for Grading the Severity of Adult and Pediatric AEs: Grade 3 is "severe"; Grade 4 is "potentially life-threatening." ULN, upper limit of normal; LDL, low-density lipoprotein; PC, platelet count.

  Baseline (Day 1) until Week 48

Secondary Outcomes (28)

• Plasma Ritonavir (RTV) AUC (0-τ)

  Week 48

• Plasma RTV Cmax

  Week 48

• Plasma RTV Cτ

  Week 48

• Plasma RTV CL/F Following Dosing Expressed in mg/kg

  Week 48

• Plasma RTV CL/F Following Dosing Expressed in mg

  Week 48

Study Arms (2)

2 - 18 yrs old (FPV/RTV BID)

EXPERIMENTAL

Cohort 1B - 2 - less than 6yrs old (FPV/RTV BID) Cohort 2 - 6 to less than 12 yrs old (FPV/RTV BID) Cohort 3 - 12 - 18 yrs old (FPV/RTV BID) Cohort 4 - 2 - 18 yrs (FPV/RTV BID)

Drug: LEXIVA (GW433908); Drug: Ritonavir

2 - less than 6yrs old (FPV BID)

EXPERIMENTAL

Cohort 1A - 2 - less than 6yrs old (FPV BID)

Drug: LEXIVA (GW433908)

Interventions

LEXIVA (GW433908) DRUG

Fosamprenavir suspension or tablet bid

2 - 18 yrs old (FPV/RTV BID); 2 - less than 6yrs old (FPV BID)

Ritonavir DRUG

Ritonavir solution bid

Also known as: LEXIVA (GW433908)

2 - 18 yrs old (FPV/RTV BID)

Eligibility Criteria

• Age: 2 Years - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Males or females 2 to 18 years of age Cohorts 1A and 1B, up to one month before 6th birthday at Baseline/Day 1 Cohort 2, up to one month before 12th birthday at Baseline/Day 1 Cohort 3, up to one month before 19th birthday at Baseline/Day 1
• A female is eligible to enter and participate in this study if she is of:
• non-childbearing potential (i.e., physiologically incapable of becoming pregnant, including any female who is pre-menarchial); or,
• 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). Premenarchial females who develop child-bearing potential while on the study will be expected to follow one of the methods of contraception listed below.
• Agreement for 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 counseled and be willing to use one of the contraception 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.
• Hormonal contraception is not recommended, due to decreased efficacy of contraception as well as increased risk of hepatic transaminase elevation (see Section 8.2).
• All subjects of childbearing potential or developing child-bearing potential while participating in this study should be counseled 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 \>=400copies/mL.
• Subjects must meet one of the following criterion:
• Antiretroviral therapy (ART)-naïve or PI-naïve subjects (defined as having received less than one week of any PI and any length of therapy with Nucleoside Reverse Transcriptase Inhibitors (NRTIs) and/or Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)).
• PI-experienced subjects (defined as having received greater than one week prior PI therapy 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 age

You may not qualify if:

• Prior history of having received APV or FPV for \>7 days.
• NNRTI use within 14 days prior to study drug administration or anticipated need for concurrent NNRTI therapy during the treatment period of the study.
• Subjects 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 infection, such treatment not being contraindicated with FPV, and the 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.
• Pregnant or lactating females.
• Presence of any serious medical condition (e.g., hemoglobinopathy, chronic anemia, a history of insulin resistance, diabetes, cardiac dysfunction, hepatitis or clinically relevant pancreatitis) which, in the opinion of the investigator, might compromise the safety of the subject.
• Grade 3 or 4 transaminase levels (ALT and/or AST) within 28 days prior to study drug administration and/or clinically relevant episodes of hepatitis within the previous 6 months.
• 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 at screen would exclude a subject from study participation.
• 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:
• Drugs whose plasma concentration may be increased to unsafe levels when co-administered with FPV including:
• Amiodarone, astemizole, bepridil, cisapride, dihydroergotamine, ergonovine, ergotamine, flecainide, halofantrine, lidocaine, lovastatin, methylergonovine, midazolam, pimozide, propafenone, quinidine, simvastatin, terfenadine, and triazolam
• Drugs with the potential to significantly decrease plasma APV concentrations including:

Sponsors & Collaborators

• ViiV Healthcare: lead
• GlaxoSmithKline: collaborator

Study Sites (39)

GSK Investigational Site

Birmingham, Alabama, 35233, United States

Location

GSK Investigational Site

Los Angeles, California, 90033, United States

Location

GSK Investigational Site

Oakland, California, 94609, United States

Location

GSK Investigational Site

Jacksonville, Florida, 32209, United States

Location

GSK Investigational Site

Tampa, Florida, 33606, United States

Location

GSK Investigational Site

Boston, Massachusetts, 02115-5724, United States

Location

GSK Investigational Site

Boston, Massachusetts, 02118, United States

Location

GSK Investigational Site

New Hyde Park, New York, 11042, United States

Location

GSK Investigational Site

New York, New York, 10016, United States

Location

GSK Investigational Site

New York, New York, 10021, United States

Location

GSK Investigational Site

New York, New York, 10037, United States

Location

GSK Investigational Site

The Bronx, New York, 10457, United States

Location

GSK Investigational Site

Durham, North Carolina, 27710, United States

Location

GSK Investigational Site

Philadelphia, Pennsylvania, 19134, United States

Location

GSK Investigational Site

Dallas, Texas, 75235, United States

Location

GSK Investigational Site

Fort Worth, Texas, 76104, United States

Location

GSK Investigational Site

Antwerp, 2020, Belgium

Location

GSK Investigational Site

Vancouver, British Columbia, V6H 3N1, Canada

Location

GSK Investigational Site

Winnipeg, Manitoba, R3E 3P4, Canada

Location

GSK Investigational Site

Toronto, Ontario, M5G 1X8, Canada

Location

GSK Investigational Site

Montreal, Quebec, H3T 1C5, Canada

Location

GSK Investigational Site

Bucharest, 021105, Romania

Location

GSK Investigational Site

Bucharest, 030303, Romania

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

Coronationville, Gauteng, 2112, South Africa

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

GSK Investigational Site

Barcelona, 08003, Spain

Location

GSK Investigational Site

Barcelona, 08950, Spain

Location

GSK Investigational Site

Madrid, 28041, Spain

Location

GSK Investigational Site

Madrid, 28046, Spain

Location

GSK Investigational Site

Málaga, 29010, Spain

Location

GSK Investigational Site

Palma de Mallorca, 07014, Spain

Location

GSK Investigational Site

Seville, 41013, Spain

Location

GSK Investigational Site

Valencia, 46009, Spain

Location

GSK Investigational Site

Vigo ( Pontevedra), 36204, Spain

Location

Related Publications (3)

• Voronin E, Fortuny C, Perez-Tamarit D, et al. Pharmacokinetics, safety and antiviral activity of fosamprenavir-containing regimens in HIV-infected 2 to 18 year-old children (48-week data, Study APV29005, a prospective, open-label, multi-centre, 48-week cohort study). Presented at: AIDS 2012 - 19th International AIDS Conference; July 22-27, 2012; Washington, DC.

  BACKGROUND

• Ross L, Cotton M, Cassim H, et al. HIV-1 drug resistance and mutational profile in fosamprenavir-treated HIV-infected children aged 2 months to 18 years at start of therapy. Presented at: AIDS 2012 - 19th International AIDS Conference; July 22-27, 2012; Washington DC.

  BACKGROUND

• Fortuny C, Duiculescu D, Cheng K, Garges HP, Cotton M, Tamarirt DP, Ford SL, Wire MB, Givens N, Ross LL, Lou Y, Perger T, Sievers J. Pharmacokinetics and 48-week safety and antiviral activity of fosamprenavir-containing regimens in HIV-infected 2- to 18-year-old children. Pediatr Infect Dis J. 2014 Jan;33(1):50-6. doi: 10.1097/INF.0b013e3182a1126a.

  PMID: 23811744 RESULT

MeSH Terms

Conditions

Infections; 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; 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

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: August 6, 2004
• First Posted: August 10, 2004
• Study Start: July 1, 2004
• Primary Completion: March 1, 2011
• Study Completion: July 1, 2013
• Last Updated: March 7, 2017
• Results First Posted: June 21, 2012

Record last verified: 2017-01

Locations

ES (9); US (16); ZA (4); CA (4); BE (1); RO (2); RU (3)