Dose Optimisation of Stavudine for the Treatment of HIV Infection (D4T)

January 28, 2016 updated by: Willem Daniel Francois Venter

A Randomised, Double-Blind, Multi-Centre, Parallel-Group Phase 3b Study to Demonstrate Non-inferiority of Stavudine (20 mg Twice Daily) Compared With Tenofovir Disoproxil Fumarate (300 mg Once Daily) When Administered in Combination With Lamivudine and Efavirenz in Antiretroviral-Naive Patients Infected With HIV-1

The purpose of this study is to demonstrate whether low dose stavudine (d4T) is non-inferior (in terms of both viral suppression and toxicity) to tenofovir (TDF) after 2 years of HIV treatment.

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 is randomised, placebo-controlled, double-blind, parallel-group, multisite, study to demonstrate whether low dose stavudine (d4T) is non-inferior to tenofovir (in terms of both viral suppression and toxicity) to tenofovir (TDF) after 2 years of HIV treatment. If so, this will allow approximately two people requiring antiretrovirals to be treated for the price of one, with the same outcomes at two years. This is of huge public health consequence in Southern Africa, where TDF and zidovudine (AZT) now consume the majority of the antiretroviral budget. Decreasing total drug doses of antiretroviral agents, while maintaining efficacy, represents an untapped possibility for decreasing costs and toxicity, if efficacy can be maintained. Stavudine (d4T), an NRTI, is currently the second most commonly used antiretroviral worldwide in developing countries. Stavudine is an ideal candidate for assessment because of low cost, widespread use, and co-formulation, albeit at a dose that has significant side effects. While well tolerated in the short term, dose-dependent medium and long-term side effects, namely lipoatrophy and peripheral neuropathy, are very common. lipoatrophy is insidious, largely irreversible, and highly stigmatising, These toxicities have lead to the withdrawal of Stavudine as a recommended drug in most countries that can afford an alternative, even in second and subsequent regimens; the World Health Organisation (WHO) recommends that countries, wherever possible, move away from using Stavudine. However, there are data that suggest a lower dose of Stavudine would be better tolerated than the currently recommended dose and will be as effective in suppressing viral load as currently preferred first-line drugs. Consented patients will be randomised into one of two treatment arms using the interactive voice response systems (IVRS). The study monitor will maintain current personal knowledge of the study through observation, review of study records and source documentation, and discussion of the conduct of the study with the principal investigator or sub investigator and staff. Data will be captured onto electronic data capture system and managed for completeness, consistency and accuracy. All study operations such as patient recruitment, data management, safety reporting will be guided by Standard Operating Procedure (SOP) documents. A total of 1068 male and female antiretroviral-naive patients infected with HIV-1 will be randomised in a 1:1 ratio (approximately 534 patients per treatment group) to Treatment Group 1 (d4T/3TC+EFV) or Treatment Group 2 (TDF/3TC+EFV). Approximately 15% of patients are expected not to be evaluable for the PP set, therefore resulting in 907 patients for the PP set. This will provide 90% power to show non-inferiority between the 2 treatment groups for the proportion of patients achieving the primary efficacy endpoint (undetectable plasma HIV-1 RNA levels [<50 copies/mL] at Week 48) for the PP set (and 94% power for the all-randomised set), using a non-inferiority margin of 10% and a 1-sided 2.5 significance level. The proportion of patients achieving the primary efficacy endpoint has been assumed to be 70% in both treatment groups. The sample size calculation has been adjusted to allow for stopping at 2 interim analyses.

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.
1077

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 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • India
    • Tamil Nadu
      • Chennai, Tamil Nadu, India, 600113
        • VHS-YRG Care Medical Centre
  • South Africa
    • Gauteng
      • Johannesburg, Gauteng, South Africa, 2196
        • Charlotte Maxeke Johannesburg Academic Hospital
  • Uganda
      • Kampala, Uganda, 25641
        • The Infectious Disease Institute (IDI), Mulago Hospital Complex

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

Yes

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Patient is male or female aged ≥18 years (upper limit of <65 years in India)
  • Patient has a documented laboratory diagnosis of infection with HIV-1 (positive enzyme-linked immunosorbent assay HIV-1 antibody test) at screening or from previous records
  • Patient has a life expectancy of ≥2 years in the opinion of the investigator
  • Patient has a plasma HIV-1 RNA level >1000 copies/mL
  • Patient has a plasma CD4 count ≤ 350 cells/mm3 using standard flow cytometry.

  • Patient has the following clinical chemistry and haematological laboratory results:

    • Serum creatinine ≤1.5 mg/dL (133 μmol/L) and a calculated creatinine clearance level ≥60 mL/min according to the Cockcroft-Gault formula
    • Serum alanine aminotransferase <5 × upper limit of normal (ULN)
    • Serum aspartate aminotransferase <5 × ULN
    • Serum lipase ≤1.5 × ULN
    • Total bilirubin ≤1.5 mg/dL (25 μmol/L) unless felt by clinician to be due to Gilbert syndrome
    • Haemoglobin ≥7.0 g/dLAbsolute neutrophil count ≥500/mm3
    • Platelet count ≥50 000/mm3.
  • Female patients of childbearing potential, including those who are less than 2 years post-menopausal, must agree to, and comply with using a highly effective method of birth control (eg, barrier contraceptives [condom or diaphragm with a spermicidal gel], hormonal contraceptives [implants, injectable, combination oral contraceptives, transdermal patches, or contraceptive rings], intrauterine devices, or sexual abstinence) while participating in this study. In addition, all women of childbearing potential must agree to continue to use birth control throughout the study until last study visit Women Not of Childbearing Potential are women who are postmenopausal or permanently sterilised (e.g. tubal occlusion, hysterectomy, bilateral salpingectomy).
  • Women of Childbearing Potential (WOCBP) - Any female who has experienced menarche and does not meet the criteria for "Women Not of Childbearing Potential".
  • Patient has the ability to comprehend the full nature and purpose of the study, in the opinion of the investigator, including possible risks and side effects, to cooperate with the investigator, to understand verbal and written instructions, and to comply with the requirements of the entire study
  • Patient is informed of the full nature and purpose of the study, including possible risks and side effects, given ample time and opportunity to read and understand this information, and sign and date the written informed consent before inclusion in the study

Exclusion Criteria:

  • Patients who have previously received treatment with any form of antiretroviral therapy, including preventing mother-to-child transmission regimens

  • Patients who are taking and cannot discontinue the following prohibited concomitant medications at least 1 week prior to the baseline visit and for the duration of the study period:

    • Any agents with significant nephrotoxic potential
    • Probenecid
    • Systemic chemotherapy agents
    • Drugs that have significant interactions with EFV other than rifampicin Administration of any of the above medications should be discontinued at least 1 week prior to the baseline visit and for the duration of the study period.
  • Patients who are clinically unstable, in the investigator's opinion, should be stabilized prior to inclusion into this study and their baseline concomitant medications should be stable for at least 1 month (30 days) prior to enrolment. In addition, investigators should not anticipate changing dose levels or medications for the duration of the study. Patients who, in the investigator's opinion, require HIV-related prophylaxis (such as cotrimoxazole) and/or other HIV-related treatments (e.g. treatment for oral thrush, tuberculosis, etc) and who, in the investigator's opinion are clinically stable may have such treatment initiated or discontinued during the screening period. The 30-day waiting period will not apply to the latter.
  • Patients who have a current history of drug or alcohol abuse that, in the opinion of the investigator, may be an impediment to patient adherence to the protocol
  • Patients who have a medical history or evidence of gastrointestinal malabsorption syndrome, chronic nausea, or vomiting which may prevent patients receiving oral medication
  • Patients who have participated in a study with an investigational drug within 60 days of screening or who are currently receiving treatment with any other investigational drug or device
  • Patients who are hepatitis B surface antigen positive
  • Patients with symptomatic peripheral neuropathies
  • Female patients who are currently pregnant or breastfeeding
  • Female patients desiring pregnancy during the next 2 years
  • Patients who have a strong likelihood of relocating far enough to make access to the study site difficult

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: Double

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
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.
Active Comparator: Stavudine
Stavudine 20mg twice daily for 96 weeks
Drug: Stavudine
Stavudine 20mg twice daily for 96 weeks + Placebo 300mg once daily for 96 weeks + Lamivudine 150mg twice daily for 96 weeks + Efavirenz 600mg once daily for 96 weeks
Other Names:
  • d4t
Active Comparator: Tenofovir Disoproxil Fumarate
Tenofovir 300mg once daily for 96 weeks
Drug: Tenofovir Disoproxil Fumarate
TDF 300mg once daily + Placebo 20mg twice daily for 96 weeks + Lamivudine 150mg twice daily for 96 weeks + Efavirenz 600mg once daily for 96 weeks
Other Names:
  • TDF

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
Time Frame
Number of participants with undetectable plasma HIV-1 RNA levels
Time Frame: Week 48
Week 48
Number of participants with adverse events related to treatment
Time Frame: Week 48
Week 48

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
Time Frame
Number of patients with plasma HIV-1 RNA levels <200 copies
Time Frame: Week 96
Week 96
Number of participants with abnormal Bone mineral density and fat distribution
Time Frame: Week 96
Week 96
Number of participants with abnormal Bone mineral density.
Time Frame: Week 96
Week 96
Number of participants with abnormal fat distribution
Time Frame: Week 96
Week 96

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.
Willem Daniel Francois Venter

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Bill and Melinda Gates Foundation

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Francois Venter, FCP (SA), Wits Reproductive Health & HIV Institute

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.
July 1, 2012

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.
December 1, 2014

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.
December 1, 2015

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).
January 22, 2016

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.
January 28, 2016

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.
February 2, 2016

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.
February 2, 2016

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.
January 28, 2016

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.
January 1, 2016

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.
  • WRHI001
  • BMGF (Other Grant/Funding Number: OPP1032239)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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