TMC114-C213: A Phase II Randomized, Controlled, Partially Blinded Trial to Investigate Dose-response of TMC114/RTV in 3-class-experienced HIV-1 Infected Patients, Followed by an Open-label Period on the Recommended Dose of TMC114/RTV.

June 2, 2011 updated by: Tibotec Pharmaceuticals, Ireland

A Phase II Randomized, Controlled, Partially Blinded Trial to Investigate Dose-response of TMC114/RTV in 3-class-experienced HIV-1 Infected Subjects, Followed by an Open-label Period on the Recommended Dose of TMC114/RTV.

The purpose of this study is to determine the antiviral activity, safety and tolerability of TMC114, formulated as an oral tablet, and administered with a low dose of ritonavir

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

This trial consists of two parts: a partially blinded dose-finding part followed by an open-label part with the recommended dose of TMC114/RTV. The dose-finding part of this trial consisted of a randomized controlled (standard of care), partially blinded, Phase II trial to determine the antiviral activity, safety and tolerability of TMC114, formulated as an oral tablet, and administered with a low dose of ritonavir. The pharmacokinetics of TMC114 are also assessed.Three hundred HIV-1 infected patients who were three-class-experienced and who were on a stable PI-containing regimen at screening for at least 8 weeks and who had plasma HIV-1 RNA > 1000 copies/mL were eligible. Three-class experience was defined as prior treatment with ³ 2 NRTIs for at least 3 months in total and ³ 1 NNRTI as part of a failing regimen. In addition, patients had to have received at least one PI for at least 3 months in the past and had to have at least 1 primary PI mutation (according to IAS definitions) at screening.As soon as all results to determine eligibility were available, and no later than 2 weeks prior to the baseline visit, the patients were randomized to one of 4 TMC114/RTV treatment groups or to a control group (standard of care). At baseline, patients changed to an investigator selected PI(s) regimen or TMC114/RTV plus optimized background regimen (OBR) consisting of NRTIs with or without T-20.In the dose-finding part of the trial, the primary objective of the trial was to evaluate the dose-response relationship in antiviral activity between the TMC114 /RTV treatment groups at 24 weeks. The recommended dose has been selected based on two joint interim analyses of this trial and of a similar trial (TMC114-C202, conducted in the United States of America, Puerto Rico, and Argentina) including approximately 150 patients in each of the two dose-finding trials (TMC114-C202 + TMC114-C213) who reached Weeks 16 and 24 or dropped out earlier. The Week 24 interim analysis included a total of 497 patients, of whom 329 had reached Week 24 or discontinued earlier. Based on the results of these two joint interim analyses, TMC114/RTV 600/100 mg b.i.d. was selected as the recommended dose for the open-label part of this trial and for future trials in treatment-experienced HIV-1 infected patients. The recommended dose of TMC114/RTV was not communicated to the investigators until the data cut-off date for the primary efficacy analysis of the two dose-finding trials was reached.The primary efficacy analysis was performed when approximately 300 patients in this trial reached 24 weeks of treatment or discontinued earlier (i.e., the primary endpoint, which was reached on 1 February 2005; A total of 318 patients were included in the analysis of whom 301 reached Week 24 or discontinued earlier). In this primary efficacy analysis, all TMC114 groups were compared to the control group by means of the confirmed virologic response at Week 24, defined as a drop in viral load of at least 1 log10 versus baseline. This primary efficacy analysis confirmed that TMC114/RTV 600/100 mg b.i.d. is the recommended dose for treatment-experienced HIV-1 infected patients.After the primary endpoint of the trial was reached (1 February 2005), and after approval of the related protocol amendment by the relevant IEC/IRB and authorities, the patients in the TMC114/RTV groups were instructed to switch to the recommended dose of TMC114/RTV (600/100 mg b.i.d.) in the open-label part of the trial.In addition, long term safety, tolerability and the durability of antiviral activity of TMC114/RTV over 144 weeks in 3-class-experienced HIV-1 infected patients will be evaluated. The trial includes a screening period of a maximum of 6 weeks, and a 144-week treatment period followed by a 4-week follow-up period. The maximum duration of the trial will be 154 weeks.Tibotec will provide follow-up treatment with TMC114/RTV for all patients who continue to benefit from treatment with TMC114/RTV. TMC114 will be provided until the drug is commercially available or until its development is discontinued.The patient will remain on the study until he/she no longer benefits from TMC114/RTV, as judged by the investigator, or he/she meets one of the withdrawal criteria. Dose-finding part of the trial: 400 mg/100 mg q.d. TMC114/RTV or 800 mg/100 mg q.d. TMC114/RTV or 400 mg/100 mg b.i.d. TMC114/RTV or 600 mg/100 mg b.i.d. TMC114/RTV. Open-label part of the trial: 600 mg/100 mg b.i.d. TMC114/RTV. Total treatment duration of 144 weeks.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
334

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Patients with documented HIV-1 infection
  • Patients receiving a PI-containing regimen at screening initiated at least 8 weeks prior to screening with plasma HIV-1 RNA > 1000 copies/mL
  • Prior use of more than 1 NRTI for at least 3 months in total
  • Prior use of one or more NNRTIs (investigational included) as part of a failing regimen
  • Patients having at least 1 primary PI mutation at screening as defined by the IAS guidelines (D30N, M46I/L, G48V, I50V/L, V82A/F/T/S, I84V, L90M)16
  • patients experienced to at least one PI for a total period of at least 3 months
  • Patients voluntarily signs the informed consent form
  • Patients can comply with the protocol requirements
  • Patients having a general medical condition that, in the investigator's opinion, does not interfere with the assessments and the completion of the trial.

Exclusion Criteria:

  • Presence of any currently active AIDS defining illness with the following exceptions, which must be discussed with the sponsor prior to enrollment: Stable cutaneous Kaposi's Sarcoma (i.e. no pulmonary or gastrointestinal involvement other than oral lesions) that is unlikely to require any form of systemic therapy during the trial. Wasting syndrome due to HIV infection if, in the investigator's opinion, it is not actively progressive and its treatment does not require hospitalization or compromise the patient's safety or compliance to adhere to the study protocol procedures. If patients are on maintenance therapy (which may include human Growth Hormone, appetite stimulants and anabolic steroids) for previously diagnosed wasting, they may be eligible for the trial only if such treatment is not included in the list of disallowed medications
  • Current or past history of alcohol and/or drug use which, in the investigator's opinion, would compromise the patient's safety or compliance to the study protocol procedures
  • patients on a treatment interruption at screening
  • patients for whom an investigational ARV is part of the regimen at screening, (with the following exceptions: T-20, FTC, atazanavir and fos-amprenavir) or use of any other non-ARV investigational agents at least 90 days prior to screening
  • Use of disallowed concomitant therapy
  • Previously demonstrated clinically significant allergy or hypersensitivity to any of the excipients of the investigational medication (TMC114/RTV/placebo)
  • Life expectancy of less than 6 months
  • 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 from screening until at least 14 days after the end of the treatment period
  • Patients with clinical or laboratory evidence of active liver disease, liver impairment/dysfunction or cirrhosis irrespective of liver enzyme levels
  • Any active or unstable medical condition (e.g. TB
  • cardiac dysfunction
  • acute viral infections) or findings during screening of medical history or physical examination that, in the investigator's opinion, would compromise the patients safety or outcome of the study
  • Patients with the following laboratory abnormalities as defined by ACTG grading scheme Renal impairment: serum creatinine grade 2 or greater (> 1.5 x ULN)
  • Lipase grade 2 or greater (> 1.5 x ULN)
  • Hemoglobin toxicity grade 2 or greater (£ 7.9 g/dL)
  • Platelet count grade 2 or greater (< 75000/mm³)
  • Absolute neutrophil count grade 2 or greater (£ 999/mm3)
  • ALT, AST grade 2 or greater (>2.5 x ULN)
  • Total bilirubin grade 2 or greater (> 1.5 x ULN) unless clinical assessment foresees an immediate health risk to the patient. For patients receiving indinavir or atazanavir at screening the total bilirubin may not exceed 3 x ULN
  • Any grade 3 or 4 toxicity with the following exceptions unless clinical assessment foresees an immediate health risk to the patient: Patients with pre-existing diabetes or assessments under non-fasted conditions who experienced a glucose grade 3 or 4, Patients with triglyceride or cholesterol elevation of grade 3 or 4 under non-fasted conditions, Patients who experienced asymptomatic triglyceride or cholesterol elevations of grade 3 or 4, patients who experienced an asymptomatic and isolated GGT grade 3 or 4 elevation with all other LFTs and bilirubin within normal ranges
  • Patients who have been randomized to a TMC114 treatment arm in a previous TMC114 trial.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
The primary objective of the trial is to compare all TMC114/RTV dose groups with control at Week 24 (the primary endpoint) by means of the confirmed virologic response, defined as a drop in viral load of at least 1 log10 versus baseline.

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
To evaluate safety and tolerability over 24 to 144 weeks; To evaluate the durability of the antiviral activity; To investigate the dose-response by comparing the different TMC114/RTV dosages.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Tibotec Pharmaceuticals, Ireland

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
October 1, 2003

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
February 1, 2005

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
July 1, 2007

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
March 28, 2008

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
March 28, 2008

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
April 2, 2008

Study Record Updates

Last Update Posted (Estimate)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
June 15, 2011

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
June 2, 2011

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
June 1, 2011

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • CR006775

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