Safety and Efficacy of Tenofovir DF in HIV-1 Infected Adolescents Failing Their Current Antiretroviral Therapy

HIV Infections Clinical Trial

Official title:

A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of the Safety and Efficacy of Tenofovir DF as Part of an Optimized Antiretroviral Regimen in HIV-1-Infected Adolescents

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00352053
• Other study ID #: GS-US-104-0321
• Status: Completed
• Phase: Phase 3
• First received: July 13, 2006
• Last updated: June 15, 2015
• Start date: June 2006
• Est. completion date: December 2013

Study information

• Verified date: June 2015
• Source: Gilead Sciences
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationBrazil: Ministry of HealthPanama: Commemorative Institute GORGAS of Studies of Health
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to assess the safety and efficacy of tenofovir disoproxil fumarate (tenofovir DF; TDF) plus a genotype-guided optimized background regimen (OBR) compared to placebo plus OBR in the treatment of human immunodeficiency virus type 1 (HIV-1) infected antiretroviral treatment-experienced adolescents with plasma HIV-1 ribonucleic acid (RNA) levels greater than or equal to 1000 copies/mL.

Description:

This is a 48-week, randomized, double-blind, placebo-controlled, multicenter study of the safety and efficacy of tenofovir DF as part of an optimized antiretroviral regimen in HIV-1 infected adolescents (12 years to < 18 years of age) who are failing their current antiretroviral regimen and have HIV-1 RNA levels ≥ 1000 copies/mL at screening. Data from three consecutive 96-week study extensions have been used to evaluate the long-term efficacy, safety, and tolerability of open-label tenofovir DF as part of an antiviral regimen, providing data for up to 336 weeks of total drug exposure.

Pretreatment:

HIV-1 genotyping will be performed as part of the screening assessments to assist in the construction of an OBR, defined as at least 3, but no more than 5 antiretroviral agents, not including tenofovir DF or placebo.

Randomized Phase:

Participants will be randomized in a 1:1 ratio to receive either tenofovir DF + OBR, or placebo + OBR. The majority of efficacy and safety assessments will be performed at each clinic visit (Weeks 4, 8, 16, 24, 32, 40, and 48). At Week 24, participants who are adherent to study drug (in the opinion of the investigator), but do not demonstrate a ≥ 0.5 log10 copies/mL decrease from baseline in HIV-1 RNA, will be considered to be nonresponders and will be unblinded. Nonresponders randomized to the placebo group will be given the option to continue on study and receive open-label tenofovir DF with an appropriate background regimen determined by the investigator. Nonresponders randomized to the tenofovir DF treatment group will be discontinued from the study.

Extension Phases:

After completing 48 weeks of double-blind treatment with tenofovir DF or placebo, participants who have not reached 18 years of age, and who, in the opinion of the investigator, would derive clinical benefit from the use of open-label tenofovir DF, will be given the option to continue (or initiate) treatment with open-label tenofovir DF in the first of three 96 week study extension periods. Nonresponders who receive open-label tenofovir DF after Week 24 will also be considered eligible for the first study extension if they met the above criteria at Week 48.

After completing the first 96 week study extension, participants who have not reached 18 years of age, and who have shown ongoing clinical benefit from tenofovir DF, will be given the option to continue receiving open-label tenofovir DF for an additional 96 weeks or until tenofovir DF became commercially available in the country where the participants are enrolled, whichever occurs first.

After completing the second 96 week study extension, participants who have not reached 18 years of age, and who have shown ongoing clinical benefit from tenofovir DF, will be given the option to continue receiving open-label tenofovir DF for an additional 96 weeks or until tenofovir DF became commercially available in the country where the participants are enrolled, whichever occurs first.

Presentation of data:

After the randomized phase of the study, participants randomized to placebo during the randomized phase of the study and then switch to open-label tenofovir DF will have their baseline reset (defined as open-label baseline), and only outcome data collected after (on/after for adverse events (AEs)/concomitant medications) participants receive their first dose of open-label tenofovir DF will be included.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 87
• Est. completion date: December 2013
• Est. primary completion date: September 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 12 Years to 17 Years

Eligibility

Major Inclusion Criteria:

• Weight = 35 kg

• Documented laboratory diagnosis of HIV infection

• Plasma HIV-1 RNA = 1000 copies/mL

• Prior antiretroviral treatment experience with at least 2 antiretroviral drug classes

• Naive to tenofovir DF

• Absence of K65R mutation on genotypic testing

Exclusion Criteria:

• Patients requiring didanosine in background regimen

• Prior history of significant renal disease

• Prior history of significant bone disease

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• HIV Infections

Intervention

Drug:
• Tenofovir DF
Tenofovir DF 300-mg tablet, administered orally, daily + OBR
• Placebo
Tenofovir DF Placebo administered orally, daily + OBR

Locations

Country	Name	City	State
Brazil	Faculdade de Medicina - UFMG	Belo Horizonte - MG
Brazil	Santa Casa de Belo Horizonte	Belo Horizonte - MG
Brazil	Hospital e Maternidade Celso Pierro	Campinas - SP
Brazil	Universidade Estadual de Campinas - UNICAMP	Campinas - SP
Brazil	Centro de Doenças Infecciosas e Parasitárias	Campo Grande - MS
Brazil	Hospital das Clinicas da Universidade Federal do Parana - UFPR	Curitiba - PR
Brazil	Hospital Infantil Joana de Gusmão	Florianópolis - SC
Brazil	Hospital Municipal Sao Jose	Joinville - SC
Brazil	Hospital Materno Infantil Professor Fernando Figueira- IMIP	Recife
Brazil	Hospital dos Servidores do Estado	Rio de Janeiro
Brazil	Hospital Geral de Nova Iguacu Ambulatorio de DST e AIDS	Rio de Jeneiro
Brazil	Hospital Guilherme Alvaro	Santos
Brazil	NEIMPE - Dept of Pediatrics Hospital das Clinicas FMRP-USP	Sao Paulo
Brazil	Instituto da Crianca do Hospital das Clinicas da FMUSP Depto de Pediatria	Sao Paulo - SP
Brazil	Instituto de Infectologia Emilio Ribas	Sao Paulo - SP
Brazil	Universidade Federal de Sao Paulo	Vila Clementino
Brazil	Hospital Infantil Nossa Senhora da Gloria Servico de Infectologia Pediatria	Vitoria - ES
Panama	Hospital del Nino	Panama City

Sponsors (1)

Lead Sponsor	Collaborator
Gilead Sciences

Countries where clinical trial is conducted

Brazil,  Panama, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time-weighted Average Change From Baseline Through Week 24 (DAVG24) in Plasma HIV-1 RNA	DAVG24 was defined as the time-weighted average between the first postbaseline value through the last value up to Week 24 minus the baseline value. DAVG24 was calculated using the trapezoidal rule with all available postbaseline data minus the baseline value.; Data for participants who discontinued the randomized (double-blind) phase of the study early were included up until the point of study discontinuation (missing data not imputed).	Baseline to 24 Weeks	No
Secondary	Time-weighted Average Change From Baseline Through Week 48 (DAVG48) in Plasma HIV-1 RNA	DAVG48 was defined as the time-weighted average between the first postbaseline value through the last value up to Week 48 minus the baseline value. DAVG48 was calculated using the trapezoidal rule with all available postbaseline data minus the baseline value.; Data for participants who discontinued the double-blind phase of the study early were included up until the point of discontinuation from the study (ie, missing data were not imputed).	Baseline to 48 weeks	No
Secondary	Change From Baseline to Week 24 in HIV-1 RNA		Baseline to 24 weeks	No
Secondary	Change From Baseline to Week 48 in HIV-1 RNA		Baseline to 48 weeks	No
Secondary	Change From Baseline to Week 96 in HIV-1 RNA		Baseline to 96 weeks	No
Secondary	Change From Baseline to Week 144 in HIV-1 RNA		Baseline to 144 weeks	No
Secondary	Change From Baseline to Week 192 in HIV-1 RNA		Baseline to 192 weeks	No
Secondary	Change From Baseline to Week 240 in HIV-1 RNA		Baseline to 240 weeks	No
Secondary	Change From Baseline to Week 288 in HIV-1 RNA		Baseline to 288 weeks	No
Secondary	Change From Baseline to Week 336 in HIV-1 RNA	No analysis was performed because the last study participant discontinued after Week 294 and the study was closed.	Baseline to 336 weeks	No
Secondary	Change From Baseline to Week 24 in Cluster Determinant 4 (CD4) Count		Baseline to 24 weeks	No
Secondary	Change From Baseline to Week 48 in CD4 Count		Baseline to 48 weeks	No
Secondary	Change From Baseline to Week 96 in CD4 Count		Baseline to 96 weeks	No
Secondary	Change From Baseline to Week 144 in CD4 Count		Baseline to 144 weeks	No
Secondary	Change From Baseline to Week 192 in CD4 Count		Baseline to 192 weeks	No
Secondary	Change From Baseline to Week 240 in CD4 Count		Baseline to 240 weeks	No
Secondary	Change From Baseline to Week 288 in CD4 Count		Baseline to 288 weeks	No
Secondary	Change From Baseline to Week 336 in CD4 Count	No analysis was performed because the last study participant discontinued after Week 294 and the study was closed.	Baseline to 336 weeks	No
Secondary	Change From Baseline to Week 24 in CD4 Percentage	CD4 percentage is the percentage of total lymphocytes that are CD4 cells.	Baseline to 24 weeks	No
Secondary	Change From Baseline to Week 48 in CD4 Percentage	CD4 percentage is the percentage of total lymphocytes that are CD4 cells.	Baseline to 48 weeks	No
Secondary	Change From Baseline to Week 96 in CD4 Percentage	CD4 percentage is the percentage of total lymphocytes that are CD4 cells.	Baseline to 96 weeks	No
Secondary	Change From Baseline to Week 144 in CD4 Percentage	CD4 percentage is the percentage of total lymphocytes that are CD4 cells.	Baseline to 144 weeks	No
Secondary	Change From Baseline to Week 192 in CD4 Percentage	CD4 percentage is the percentage of total lymphocytes that are CD4 cells.	Baseline to 192 weeks	No
Secondary	Change From Baseline to Week 240 in CD4 Percentage	CD4 percentage is the percentage of total lymphocytes that are CD4 cells.	Baseline to 240 weeks	No
Secondary	Change From Baseline to Week 288 in CD4 Percentage	CD4 percentage is the percentage of total lymphocytes that are CD4 cells.	Baseline to 288 weeks	No
Secondary	Change From Baseline to Week 336 in CD4 Percentage	No analysis was performed because the last study participant discontinued after Week 294 and the study was closed.	Baseline to 336 weeks	No
Secondary	Percentage of Participants With an HIV-1 RNA Decrease of = 1.0 log10 Copies/mL From Baseline to Week 24		Baseline to 24 weeks	No
Secondary	Percentage of Participants With an HIV-1 RNA Decrease of = 1.0 log10 Copies/mL From Baseline to Week 48		Baseline to 48 weeks	No
Secondary	Percentage of Participants With an HIV-1 RNA Decrease of = 1.0 log10 Copies/mL From Baseline to Week 96		Baseline to 96 weeks	No
Secondary	Percentage of Participants With an HIV-1 RNA Decrease of = 1.0 log10 Copies/mL From Baseline to Week 144		Baseline to 144 weeks	No
Secondary	Percentage of Participants With an HIV-1 RNA Decrease of = 1.0 log10 Copies/mL From Baseline to Week 192		Baseline to 192 weeks	No
Secondary	Percentage of Participants With an HIV-1 RNA Decrease of = 1.0 log10 Copies/mL From Baseline to Week 240		Baseline to 240 weeks	No
Secondary	Percentage of Participants With an HIV-1 RNA Decrease of = 1.0log 10 Copies/mL From Baseline to Week 288		Baseline to 288 weeks	No
Secondary	Percentage of Participants With an HIV-1 RNA Decrease of = 1.0 log10 Copies/mL From Baseline to Week 336	No analysis was performed because the last study participant discontinued after Week 294 and the study was closed.	Baseline to 336 weeks	No
Secondary	Percentage of Participants With HIV-1 RNA < 400 Copies/mL at Week 24		Week 24	No
Secondary	Percentage of Participants With HIV-1 RNA < 400 Copies/mL at Week 48		Week 48	No
Secondary	Percentage of Participants With HIV-1 RNA < 400 Copies/mL at Week 96		Week 96	No
Secondary	Percentage of Participants With HIV-1 RNA < 400 Copies/mL at Week 144		Week 144	No
Secondary	Percentage of Participants With HIV-1 RNA < 400 Copies/mL at Week 192		Week 192	No
Secondary	Percentage of Participants With HIV-1 RNA < 400 Copies/mL at Week 240		Week 240	No
Secondary	Percentage of Participants With HIV-1 RNA < 400 Copies/mL at Week 288		Week 288	No
Secondary	Percentage of Participants With HIV-1 RNA < 400 Copies/mL at Week 336	No analysis was performed because the last study participant discontinued after Week 294 and the study was closed.	Week 336	No
Secondary	Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 24		Week 24	No
Secondary	Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48		Week 48	No
Secondary	Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 96		Week 96	No
Secondary	Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 144		Week 144	No
Secondary	Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 192		Week 192	No
Secondary	Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 240		Week 240	No
Secondary	Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 288		Week 288	No
Secondary	Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 336	No analysis was performed because the last study participant discontinued after Week 294 and the study was closed.	Week 336	No
Secondary	Percentage of Participants With Virologic Failure Through Week 48	Virologic failure was defined as either nonresponse or viral rebound.; Nonresponse (failure to achieve response). Response was defined as either; A = 0.5 log10 copies/mL decrease in HIV-1 RNA from baseline at 2 consecutive visits, or; HIV-1 RNA < 400 copies/mL at 2 consecutive visits.; Viral rebound was defined as either; Participants who achieved a = 0.5 log10 copies/mL decrease from baseline in plasma HIV-1 RNA at 2 consecutive visits, who then subsequently achieved plasma HIV-1 RNA values = 1.0 log10 copies/mL above their on-study nadir (lowest value) and/or plasma HIV-1 RNA values = the baseline value at 2 consecutive visits, or; Participants who achieved plasma HIV-1 RNA levels of < 400 copies/mL at 2 consecutive visits, and then subsequently had plasma HIV-1 RNA levels > 1000 copies/mL at 2 consecutive visits.; The virologic failure rate was estimated from Kaplan-Meier product limit method by including all HIV-1 RNA data collected during the double-blind phase.	Up to 48 weeks	No