TMC114-TiDP29-C230 - A Safety Study to Evaluate the Antiviral Activity of Darunavir in Combination With Ritonavir in HIV 1 Infected Adolescents Between 12 and 18 Years of Age Who Have Not Received Previous Treatment With Antiretroviral Drugs

Condition(s) targeted: HIV Infections

Intervention: darunavir tablets (Drug); ritonavir capsule (Drug)

Phase: Phase 2

Status: Recruiting

Sponsored by: Tibotec Pharmaceuticals, Ireland

Official(s) and/or principal investigator(s):
Tibotec Pharmaceuticals Limited Clinical Trial, Study Director, Affiliation: Tibotec Pharmaceutical Limited

Overall contact:
Use link at the bottom of the page to see if you qualify for an enrolling site (see list). If you still have questions:, Email: info1@veritasmedicine.com

The purpose of this Phase II trial is to evaluate pharmacokinetics ( blood levels), safety, tolerability, and efficacy of darunavir with low-dose ritonavir (DRV/rtv) administered once daily (q. d.), in combination with an investigator-selected background regimen consisting of 2 NRTIs, in treatment-naÃ-ve (never treated before) HIV 1 infected adolescents aged from 12 to < 18 years and weighing at least 40 kg

Official title: A Phase II, Open Label Trial, to Evaluate Pharmacokinetics, Safety, Tolerability and Antiviral Activity of DRV/Rtv q.d. in Treatment-naïve HIV-1 Infected Adolescents Between 12 and < 18 Year of Age

Study design: Treatment, Non-Randomized, Open Label, Single Group Assignment, Pharmacokinetics Study

Primary outcome: To evaluate the pharmacokinetics of DRV/rtv 800/100 mg q.d. in combination with an investigator-selected background regimen over a 24-week treatment period in ARV treatment-naÃ-ve HIV-1 infected adolescents from 12 to < 18 years and weighing >=40 kg

Secondary outcome:

To evaluate long-term safety, tolerability and efficacy of DRV/rtv 800/100 mg once daily. (in combination with an investigator-selected background regimen) over a 48-week treatment period in this population.

To evaluate immunology, resistance characteristics, pharmacokinetics, andpharmacokinetic/pharmacodynamic (PK/PD) relationships over 48 weeks of treatment with DRV/rtv 800/100 mg q.d. in this population.

Detailed description: TMC114-C230 is a 48-week, open-label, single-arm, Phase II trial to evaluate the pharmacokinetics, safety, tolerability, and efficacy of darunavir/ritonavir (DRV/rtv) administered once daily., in combination with other ARVs (antiretroviral), in treatment-naïve HIV-1 infected adolescents aged from 12 to < 18 years and weighing >= 40 kg. A total of 12 male and female ARV treatment-naïve HIV-1 infected adolescents are planned to be included in the trial. Patients will be considered treatment-naïve if they have never received treatment with an ARV drug, including both investigational as well as commercially available ARVs indicated for the treatment of HIV-infection and ARVs for the treatment of hepatitis B infection with anti-HIV activity (e. g., adefovir, lamivudine, emtricitabine, entecavir). Note that female adolescents who used nevirapine to prevent mother-to-child transmission (MTCT) are allowed in the trial, as long as they have never received other ARVs. Females who used zidovudine (AZT) to prevent MTCT will not be allowed as this may result in reduced susceptibility to the ARV background regimen consisting of 2 NRTIs (nucleotide reverse transcriptase inhibitor). Patients will receive the recommended dose of DRV/rtv for treatment-naïve HIV-1 infected adults, i. e., 800/100 mg q. d. (once daily), in combination with an investigator-selected background regimen to evaluate safety, tolerability, efficacy (plasma viral load and immunology), pharmacokinetics, pharmacokinetic/pharmacodynamic relationships, and resistance over 48 weeks of treatment with DRV/rtv 800/100 mg once daily. in treatment-naïve HIV-1 infected adolescents. During the first 2 weeks of the trial DRV/rtv will have to be taken in the morning to facilitate the pharmacokinetic sampling for all patients at Week 2. After completion of the 24-hour intensive pharmacokinetic sample collection at Week 2, patients will have the choice whether to take the darunavir/ritonavir (DRV/rtv) dose in the morning or in the evening. The investigator-selected background regimen will consist of 2 NRTIs and will be either zidovudine/lamivudine or abacavir/lamivudine, whichever is approved and marketed or considered local standard of care for adolescents aged from 12 to < 18 years in a particular country. The background regimen will be given as the co-formulation or as the separate components, according to local availability and use in the country. Since abacavir has been associated with severe hypersensitivity reactions, and the risk for developing such reactions has been linked to the presence of the HLA-B*5701 all, patients without prior documented HLA-B*5701 negative results in whom the investigator considers abacavir as background regimen will be tested to avoid hypersensitivity reactions. In those patients where HLA-B*5701 is tested positive, abacavir should not be administered. Substitutions of NRTIs of the background regimen for reasons of tolerability or toxicity are allowed. At all times, the background regimen should consist of 2 NRTIs and the patient's genotyping at screening should show susceptibility to the alternative NRTIs. The trial will consist of a screening period of 4 weeks, a 48-week treatment period, and a 4-week follow-up period. The primary objectives of the trial are to evaluate the pharmacokinetics, safety, tolerability and efficacy of DRV/rtv 800/100 mg q. d. in combination with an investigator-selected background regimen over a 24-week treatment period in ARV treatment-naïve HIV-1 infected adolescents aged from 12 to < 18 years and weighing >= 40 kg. Safety, efficacy, resistance, pharmacokinetic analyses, and PK/PD analyses will be performed at Week 24 (primary analysis when all patients have been treated for 24 weeks or discontinued earlier) and Week 48 (final analysis when all patients have been treated for 48 weeks or discontinued earlier).At Week 2, pharmacokinetic blood sampling will be performed in all patients at 6 time points over 24 hours. To facilitate the PK sample collection at 12 and 24 hours, hospitalization from Day 14 to the morning of Day 15 is recommended. Some centers may consider it also appropriate for patients to stay in the clinic overnight before the start of the PK sampling on Day 14. Sparse blood sampling will be performed for all patients for assessment of darunavir population pharmacokinetics at Weeks 4, 24 and 48. During the trial, patients will be seen at regular visits during which the investigator will assess the patient's medical condition, any AEs and compliance to trial medication. Laboratory evaluations for efficacy and safety will be done at regular visits. The DSMB (data safety monitoring board), composed of external experts and Sponsor representatives not directly involved in trial conduct, will also be responsible for regular monitoring and objective assessment of the safety and tolerability. Efficacy parameters will include measurements of plasma viral load, time to virologic response; time to loss of virologic response; change in CD4+ and CD8+ (absolute and %), and CD4+/CD8+ ratio at Week 24 (primary analysis) and Week 48. The primary efficacy endpoint will be a plasma viral load at Week 24. Resistance determinations (geno/phenotyping) will be performed at screening (only genotyping), baseline, Week 24, Week 48 and in the event of early withdrawal. ARV medication adherence will be assessed during the trial by means of a questionnaire and via pill count. Patients may discontinue the trial for lack or loss of response, and patients must be withdrawn if they experience a grade 4 AE or confirmed grade 4 laboratory abnormality considered to be at least possibly related to trial medication. Patients who complete the 48 weeks of treatment with darunavir/ritonavir and who continue to benefit from this treatment, will have the opportunity to continue this treatment until the patient no longer benefits from the drug, until darunavir is commercially available or can be accessed from another source (e. g., access program, government program) or until the development program is discontinued. 48-weeks, excluding screening (4 weeks) and post-treatment follow-up (4 weeks). DRV 2 x 400 mg and ritonavir 100 mg once daily (oral) in combination with an investigator-selected background regimen zidovudine/lamivudine or abacavir/lamivudine.

Minimum age: 12 Years. Maximum age: 18 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Patients with a documented HIV 1 infection

- Body weight from at least 40 kg at screening

- Screening plasma HIV 1 RNA >= 1000 copies/mL

- Parents or legal representative and trial patients (where appropriate, depending on

age and local regulation) willing and able to give consent and assent

- General medical condition, in the investigator's opinion, does not interfere with the

assessments and the completion of the trial

- Able to swallow DRV tablets (400 mg) and ritonavir capsules (100 mg)

Exclusion Criteria:

- Patients with presence of any currently active conditions included in the listing of

WHO (World Health Organisation) Clinical Stage 4

- Any condition (including, but not limited to, alcohol and drug use), which, in the

opinion of the investigator, could compromise the subject's safety or adherence to the trial protocol

- Previous or current use of ARVs ( antiretrovirals)

- Primary or acute HIV infection

- Use of any investigational agents within 30 days prior to screening

- Use of disallowed concomitant therapy

- Pregnant or breast-feeding

- Female patient of childbearing potential without use of effective non-hormonal birth

control methods or not willing to continue practicing these birth control methods for at least 30 days after the end of the treatment period

- Patients with clinical or laboratory evidence of significantly decreased hepatic

function or decompensation (i. e., liver insufficiency), irrespective of liver enzyme levels

- Any active clinically significant disease (e. g., cardiac dysfunction, pancreatitis,

acute viral infection) or findings during screening of medical history or physical examination that are expected to compromise the patient's safety or outcome in the trial

Use link at the bottom of the page to see if you qualify for an enrolling site (see list). If you still have questions:, Email: info1@veritasmedicine.com

Paris, France; Not yet recruiting

Dublin, Ireland; Recruiting

Madrid, Spain; Not yet recruiting

Esplugues De Llobregat, Spain; Recruiting

Kiev, Ukraine; Not yet recruiting

Bristol, United Kingdom; Not yet recruiting

Birmingham, United Kingdom; Not yet recruiting

Stoke On Trent, United Kingdom; Not yet recruiting

Memphis, Tennessee, United States; Recruiting

To learn how to participate in this trial please click here.

Starting date: July 2009
Ending date: December 2010
Last updated: September 25, 2009