Clinical trial NCT00089583: 48-Week Study Of GW433908 And Ritonavir Or GW433908 Alone, Twice Daily In Pediatric Patients With HIV Infection
Official title: A 48 Week, Phase II, Non-Comparative, Open-label, Multi-Cohort, Multicenter Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Antiviral Activity of GW433908/Ritonavir BID When Administered to HIV-1 Infected, PI-Naïve and Experienced, Pediatric Subjects, 2 to 18 Years Old and of GW433908 BID Administered to PI-Naïve, Pediatric Subjects 2 to < 6 Years Old
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Infection, Human Immunodeficiency Virus I
Keywords: antiretroviral therapy
pediatrics
AGENERASE
amprenavir
fosamprenavir
HIV Infection
ritonavir
protease inhibitor
LEXIVA
Lead sponsor: ViiV Healthcare
Sponsor class: INDUSTRY
Collaborators: name: GlaxoSmithKline
First posted: 2004-08-10
Enrollment: 110
Sex: ALL
Minimum age (years): 2
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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 .

Detailed description: A 48 Week, Phase II, non-comparative, open-label, multi-cohort, multicenter study to evaluate the safety, tolerability, pharmacokinetics and antiviral activity of GW433908/Ritonavir BID when administered to HIV-1 infected PI-Naive and experienced, Pediatric Subjects 2 to 18 years old and of GW433908 BID Administered to PI-Naive Pediatric subjects 2 to \<6 years old

Eligibility criteria: Inclusion criteria:

* 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:

  1. non-childbearing potential (i.e., physiologically incapable of becoming pregnant, including any female who is pre-menarchial); or,
  2. 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

Exclusion criteria:

* 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:

Carbamazepine, dexamethasone, phenobarbital, primidone, rifampin, St Johns Wort.

* Treatment with other investigational drugs/therapies (note: treatments available through a Treatment Investigational New Drug \[IND\] 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 or during the treatment period of the study.
* 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).
* Substantial non-adherence based on history

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 mg/kg
timeFrame: Week 48
measure: Plasma APV CL/F Following Dosing Expressed in mg
timeFrame: Week 48
measure: Plasma APV Tmax
timeFrame: Week 48
measure: Plasma APV t1/2
timeFrame: Week 48
measure: Number of Participants Who Permanently Discontinued the Treatment Due to Any Adverse Event (AE)
timeFrame: Week 48
measure: Change From Baseline in Triglycerides, Total Cholesterol, Low-density Lipoprotein (LDL) Cholesterol, High-density Lipoprotein (HDL) Cholesterol, and Serum Glucose at Week 48
timeFrame: Baseline (Day 1) and Week 48
measure: Change From Baseline in Serum Lipase at Week 48
timeFrame: Baseline (Day 1) and Week 48
measure: Change From Baseline in Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) at Week 48
timeFrame: Baseline (Day 1) and Week 48
measure: Number of Participants With Treatment-emergent (TE) Grade 3/4 Clinical Chemistry Laboratory Abnormalities
timeFrame: Baseline (Day 1) until Week 48
Secondary outcomes:
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 Following Dosing Expressed in mg/kg
timeFrame: Week 48
measure: Plasma RTV CL/F Following Dosing Expressed in mg
timeFrame: Week 48
measure: Plasma RTV Tmax
timeFrame: Week 48
measure: Plasma RTV t1/2
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 Following Dosing Expressed in mg/kg
timeFrame: Week 48
measure: Plasma FPV CL/F Following Dosing Expressed in mg
timeFrame: Week 48
measure: Plasma FPV Tmax
timeFrame: Week 48
measure: Plasma FPV t1/2
timeFrame: Week 48
measure: Number of Participants (Par.) With Virological Outcome (Plasma HIV-1 Ribonucleic Acid [RNA] <400 Copies/mL) at Week 48
timeFrame: Week 48
measure: Number of Participants (Par.) With Plasma HIV-1 Ribonucleic Acid (RNA) <400 Copies Per Milliliter at Baseline and Weeks 2,12, 24, and 48 (MSD=F)
timeFrame: Baseline and Weeks 2, 12, 24, and 48
measure: Median Plasma HIV-1 RNA (log10 Copies/mL) at Baseline and Weeks 2, 12, 24, and 48 (Observed Analysis)
timeFrame: Baseline and Weeks 2, 12, 24, and 48
measure: Median Change From Plasma HIV-1 RNA (log10 Copies/mL) at Weeks 2, 12, 24, and 48 (Observed Analysis)
timeFrame: Baseline and Weeks 2, 12, 24, and 48
measure: Number of Participants With at Least a 1.0 log10 HIV-1 RNA Decrease From Baseline at Weeks 2, 12, 24, and 48 (Observed Analysis)
timeFrame: Baseline and Weeks 2, 12, 24, and 48
measure: Cluster of Differentiation Antigen 4 (CD4+) Cell Count at Baseline and at Weeks 2, 12, 24, and 48
timeFrame: Baseline and Weeks 2, 12, 24, and 48
measure: Change From Baseline in CD4+ Cell Count at Weeks 2, 12, 24, and 48
timeFrame: Baseline and Weeks 2, 12, 24, and 48
measure: Percentage of Total Lymphocytes (TLs) That Are CD4+ Cells at Baseline and Weeks 2, 12, 24, and 48
timeFrame: Baseline and Weeks 2, 12, 24, and 48
measure: Change From Baseline in the Percentage of Total Lymphocytes (TLs) That Are CD4+ Cells at Weeks 2, 12, 24, and 48
timeFrame: Baseline and Week 2, 12, 24, 48
measure: Number of Confirmed Virologic Failure Participants (Par.) With Treatment-emergent HIV Genotypic Resistance in Reverse Transcriptase and Protease
timeFrame: Week 48
measure: Number of Confirmed Virologic Failure Participants (Par.) Since the Week 48 Analysis With Treatment-emergent HIV Genotypic Resistance in Reverse Transcriptase and Protease
timeFrame: After Week 48 through Week 240
measure: Number of Confirmed Virologic Failure Participants (Par.) With Treatment-emergent Reductions in Drug Susceptibility (DS)
timeFrame: Baseline through 48 Weeks
measure: Number of Confirmed Virologic Failure Participants (Par.) Since the Week 48 Analysis With Treatment-emergent Reductions in Drug Susceptibility (DS)
timeFrame: Week 60 through Week 240
measure: Number of Participants Reporting Perfect Adherence Over the 3 Days Prior to the Study Visits at Weeks 2, 12, 24, and 48 as Assessed by Study Coordinator Using the Pediatric AIDS Clinical Trials Group (PACTG) Adherence Questionnaire
timeFrame: Weeks 2, 12, 24, and 48
measure: Correlation Between Plasma APV Exposure and Plasma vRNA, CD4+ Cell Counts, and the Occurrence of Adverse Events
timeFrame: Week 48
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: GSK Investigational Site
state: Alabama
city: Los Angeles
country: United States
facility: GSK Investigational Site
state: California
city: Oakland
country: United States
facility: GSK Investigational Site
state: California
city: Jacksonville
country: United States
facility: GSK Investigational Site
state: Florida
city: Tampa
country: United States
facility: GSK Investigational Site
state: Florida
city: Boston
country: United States
facility: GSK Investigational Site
state: Massachusetts
city: Boston
country: United States
facility: GSK Investigational Site
state: Massachusetts
city: Bronx
country: United States
facility: GSK Investigational Site
state: New York
city: New Hyde Park
country: United States
facility: GSK Investigational Site
state: New York
city: New York
country: United States
facility: GSK Investigational Site
state: New York
city: New York
country: United States
facility: GSK Investigational Site
state: New York
city: New York
country: United States
facility: GSK Investigational Site
state: New York
city: Durham
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Philadelphia
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Dallas
country: United States
facility: GSK Investigational Site
state: Texas
city: Fort Worth
country: United States
facility: GSK Investigational Site
state: Texas
city: Antwerpen
country: Belgium
facility: GSK Investigational Site
city: Vancouver
country: Canada
facility: GSK Investigational Site
state: British Columbia
city: Winnipeg
country: Canada
facility: GSK Investigational Site
state: Manitoba
city: Toronto
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Montreal
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Bucharest
country: Romania
facility: GSK Investigational Site
city: Bucharest
country: Romania
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: Coronationville
country: South Africa
facility: GSK Investigational Site
state: Gauteng
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
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Malaga
country: Spain
facility: GSK Investigational Site
city: Palma de Mallorca
country: Spain
facility: GSK Investigational Site
city: Sevilla
country: Spain
facility: GSK Investigational Site
city: Valencia
country: Spain
facility: GSK Investigational Site
city: Vigo ( Pontevedra)
country: Spain
facility: GSK Investigational Site
Study officials:
affiliation: ViiV Healthcare
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.