Once a Day (QD) - Twice a Day (BID) Clinical Trial: Didanosine, Lamivudine and Efavirenz Versus Zidovudine, Lamivudine and Efavirenz in the Starting Treatment of HIV

This study has been completed.
Sponsor:
Information provided by:
Clinical Trial Agency of HIV Study Group
ClinicalTrials.gov Identifier:
NCT00256828
First received: November 21, 2005
Last updated: October 15, 2007
Last verified: November 2005
  Purpose

The purpose of this study is to compare the antiviral activity of two treatment groups for HIV chronic infection: a QD regimen of didanosine, lamivudine and efavirenz versus a BID regimen of zidovudine, lamivudine and efavirenz. Both will be administered with food in the starting treatment of human immunodeficiency virus infection at Week 48.


Condition Intervention Phase
HIV Infections
Drug: didanosine + lamivudine + efavirenz
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Multicenter, Randomized, Open Label, Clinical Trial Comparing a QD Regimen of Didanosine, Lamivudine and Efavirenz With a Standard BID Regimen of Zidovudine, Lamivudine and Efavirenz in the Starting Treatment of Human Immunodeficiency Virus Infection (GESIDA 39/03)

Resource links provided by NLM:


Further study details as provided by Clinical Trial Agency of HIV Study Group:

Primary Outcome Measures:
  • Percentage of patients with HIV-RNA levels < 50 c/ml (intent-to-treat [ITT])

Secondary Outcome Measures:
  • Percentage of patients with HIV-RNA level < 400 c/ml
  • Time to therapy failure
  • CD4 cell count increase from Baseline to Week 48 (w48)
  • Quality of life changes
  • Compliance to both treatment regimens
  • Description of adverse events

Estimated Enrollment: 360
Study Start Date: June 2004
Estimated Study Completion Date: November 2006
  Hide Detailed Description

Detailed Description:

The inhibition of HIV replication mediated by HAART causes an actual immunological reconstitution that has been clinically evidenced as a dramatic reduction in mortality, incidence of opportunistic diseases, hospital admissions and costs associated with healthcare in HIV-infected patients, which has been shown since the year 1996. Unfortunately, the eradication of HIV is not feasible with the therapies available; therefore, treatment of HIV infection is currently approached as a "life-long" strategy. HAART is not free from middle and long-term adverse events.

It must be considered that, until relatively recently, the HAART regimens required taking a high number of tablets several times daily, frequently with diet restrictions, which made compliance difficult and improved the quality of life of the patients. In any case, it must be noted that insufficient compliance with HAART can have harmful consequences for the patient, public health and health resources.

The factors predicting compliance with ART can depend on the patient, the healthcare team and the therapeutic regimen.

As mentioned above, until recent dates, HAART has gathered all factors making compliance difficult: long-term duration, over one drug, over one dose daily and presence of adverse events. Therefore, the adequate compliance is an actual challenge for patients and for the health staff and has been considered, with a good criterion, the weak point of antiretroviral treatment.

For all the above, it can be stated that the ideal HAART regimen would be that with few tablets and that could be taken once daily. The expected advantages of QD regimens could include mainly three: first, they will improve compliance, which will have a highly positive effect on the antiviral efficacy of HAART. On the other hand, QD regimens will enable that HAART is better adapted to the lifestyle of the patient and will have a low interference with working hours, so they will be more convenient and improve quality of life. Finally, it must be noted that QD regimens will enable for monitoring HAART directly, and will allow for a relatively significant group of patients in our setting to follow the treatment with a greater guarantee of success, such as those with problems of drug addiction, lack of social support, mental disease and those admitted to penitentiary centers.

The main disadvantage of QD regimens is the virtual lack of large clinical trials comparing this therapeutic approach to other potent, well-established BID regimens. Therefore, it is very interesting to examine this approach in a randomized clinical trial with an adequate design such as that proposed.

The second problem is the consequences that result of missing a dose since this could entail that for some time - in the 24 hours following the failure - the drug concentrations could decrease enough to stop inhibiting viral replication; this could also promote the emergence of viral strains resistant to the drugs. In principle, the implications of missing a dose depend substantially on the pharmacokinetic properties included in the QD regimen (Cmin, half-life, intracellular concentrations, and the IC50 of the HIV of each patient), so that, the higher the drug half-life and the higher the Cmin/IC50 ratio, the higher the probability that alter missing a dose the Cmin persists above the IC50 of the HIV strain of the patient. Therefore, it is important to select drugs with pharmacokinetic profiles and an antiviral potency enough for QD administration (vide infra).

BID regimen (efavirenz + zidovudine + lamivudine):

In this study, we have chosen as BID regimen that containing NNRTI efavirenz (Sustiva®) and Combivir® which is the commercial combination of the NRTI zidovudine + lamivudine, that will lead patients to take one tablet in the morning and 2 tablets at night. We have chosen this regimen (zidovudine + lamivudine + efavirenz) because it is the starting treatment regimen for HIV chronic infection best studied and considered by many as the gold standard for this indication.

QD regimen (efavirenz + didanosine + lamivudine):

The QD regimen will be made up by didanosine (capsule-CT) + lamivudine + efavirenz, a regimen containing three tablets that must be taken together at night and which is the QD regimen with most experience to date. We have chosen as combination of NRTI didanosine and lamivudine, drugs authorized for QD use with a very good safety profile and no interactions with each other and with efavirenz. The combination of didanosine and lamivudine is highly attractive and is in fact recommended for the starting HAART by various agencies though not at the same level as the combination of zidovudine and lamivudine (which can be only administered BID) just because there are less randomized clinical trials with the former than with the latter combination of NRTI. Therefore, one of the strengths of the study is that it proposes the possibility of assessing the combination of didanosine and lamivudine in a starting HAART regimen.

In this study, the patients allocated to the QD regimen containing didanosine (capsule-CT) + lamivudine + efavirenz will take all tablets together at night with dinner. In principle, this involves a minor deviation from the data sheet of didanosine where it is specified that the drug must be taken fasting.

Didanosine is the second antiretroviral drug marketed and, in the last decade, the presentation and dosage form of this drug have improved remarkably, from bags with buffered powder for twice daily administration, with dispersible tablets with buffer, to the current dosage form which is a gastroresistant capsule (capsule-CT) which allows for administration in once daily doses and that, since it has no buffer, has improved substantially the gastric tolerance to the drug.

The formulations of didanosine as powder or buffered dispersible tablets must be taken fasting for absorption to be optimum, since its administration with food reduces significantly drug absorption and plasma concentrations. However, the effect of food on the absorption of capsules-CT does not cause an unequivocal reduction in drug exposure.

Primary Objective:

  • To compare the antiviral activity of the two treatment groups (QD vs BID) at Week 48, based on the percentage of patients with HIV-RNA levels <50 c/ml.

Secondary Objectives:

  • To compare the percentage of patients responding to the treatment with HIV-RNA levels < 400 c/ml at Week 48, with the same approach of analysis as for the primary objective.
  • To compare the time to therapy failure at Week 48 in both treatment regimens.
  • To compare the increase in the CD4 cell levels from baseline to Week 48 in both treatment regiments.
  • To compare the impact on the quality of life of both treatment regimens.
  • To compare compliance of both treatment regimens.
  • To compare the safety and tolerance of both treatment regimens along the 48 weeks of treatment.
  • To assess the efficacy of the administration of didanosine together with food.

Randomization Procedure:

The randomization will be centralized and stratified by the baseline viral burden level, being higher or lower than 100,000 cop/ml. The patients giving their written informed consent will be included in the study. To include a patient, the clinical trial agency Gesida will be contacted by phone.

Study Procedures:

HIV-RNA, CD4 and routine labs will be collected at screening, baseline, w1, w4, w12, w24 and w48. Quality of life will be measured with a self-patient report questionnaire (MOS-HIV).

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Chronic HIV infection with plasma RNA viral burden of HIV > 2,000 copies/ml obtained in the month prior to randomization.
  • Ages 18 years or older.
  • Women with childbearing potential should use an effective contraceptive method.
  • The subjects should give their written informed consent.
  • The subjects should provide the baseline laboratory values measured during the 4 weeks prior to the start of the study drugs, specified below:

    • serum creatinine < 1.5 times the upper normal limit;
    • total amylase < 1.4 times the upper normal limit;
    • liver enzymes (AST, ALT) < 4 times the upper normal limit.

Exclusion Criteria:

  • Previous antiretroviral treatment.
  • Suspected (acute) primary HIV infection starting less than six months before.
  • Suspected or proven acute hepatitis in the 30 days prior to inclusion in the study. Subjects with chronic hepatitis are eligible provided their liver function enzymes < 4 times the upper normal limit.
  • Previous therapy with agents with a significant potential of systemic myelosuppression, neurotoxicity, pancreatotoxicity, liver toxicity or cytotoxicity in the 3 months prior to the start of the study, or expected need for requiring therapy on inclusion, or therapy with methadone or ribavirin/interferons or treatment with neurotoxic drugs or drugs affecting CYP 3A4.
  • Patients under methadone program
  • Abuse of alcohol or drugs, sufficient, in the investigator's opinion, to prevent an adequate compliance with the study treatment or that could increase the risk of developing pancreatitis or toxic hepatitis.
  • Untreatable diarrhea (> 6 loose stools/day for at least 7 consecutive days) within the 30 days prior to inclusion in the study.
  • Pregnancy or nursing.
  • History of bilateral peripheral neuropathy or signs and symptoms of bilateral peripheral neuropathy > Grade 2 on screening.
  • Inability to tolerate oral drugs.
  • Any other clinical condition or previous therapy that, in the investigator's opinion, leads the patient to be inadequate for the study or unable to comply with the dosage requirements.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00256828

  Hide Study Locations
Locations
Spain
Hospital General de Área de Elda
Elda, Alicante, Spain, 03600
Hospital de Orihuela-Vega Baja, San Bartolomé-Orihuela
Orihuela, Alicante, Spain, 03314
Hospital General-Central de Asturias
Oviedo, Asturias, Spain, 33006
Hospital Son Llatzer
Palma de Mallorca, Baleares, Spain, 07198
Hospital Son Dureta
Palma de Mallorca, Baleares, Spain, 07014
Hospital General de Granollers
Granollers, Barcelona, Spain, 08400
Hospital de Terrassa
Terrassa, Barcelona, Spain, 08227
Hospital Sant Llorenc de Viladecans
Viladecans,, Barcelona, Spain, 08840
Hospital General de Jerez de la Frontera11407
Jerez, Cadiz, Spain, 11407
Hospital Universitario Marqués de Valdecilla
Santander, Cantabria, Spain, 39008
Hospital Sierrallana de Torrelavega
Torrelavega, Cantabria, Spain, 39300
Hospital Provincial Nuestra Señora de la Montaña-Complejo Hospitalario de Cáceres
Caceres, Cáceres, Spain, 10003
Hospital Comarcal de la Selva
Blanes, Gerona, Spain, 17300
Hospital de Figueres
Figueras, Gerona, Spain, 17600
Hospital de Palamós
Palamos, Gerona, Spain, 17230
Hospital Donostia
San Sebastian, Guipuzcoa, Spain, 20014
Hospital Arquitecto Marcide
Ferrol, La Coruña, Spain, 15405
Hospital Príncipe de Asturias
Alcala de Henares, Madrid, Spain, 28880
Hospital Severo Ochoa
Leganes, Madrid, Spain, 28911
Hospital Costa del Sol
Marbella, Málaga, Spain, 29600
Hospital Meixoeiro
Vigo, Pontevedra, Spain, 36200
Hospital Xeral-Cíes de Vigo
Vigo, Pontevedra, Spain, 36204
Hospital General Universitario Sant Joan de Reus
Reus, Tarragona, Spain, 43201
Hospital de Basurto
Bilbao, Vizcaya, Spain, 48013
Hospital Universitario de San Juan de Alicante
Alicante, Spain, 03550
Hospital Santa Creu y Sant Pau
Barcelona, Spain, 08025
Hospital de Mollet
Barcelona, Spain, 08100
Hospital De Vic
Barcelona, Spain, 08500
Hospital General Vall D'Hebrón
Barcelona, Spain, 08035
Consorcio Sanitario de Mataró
Barcelona, Spain, 08304
Hospital del Mar
Barcelona, Spain, 08003
Hospital General Yagüe
Burgos, Spain, 09005
Hospital General de Castellón
Castellon, Spain, 12004
Hospital Provincial Reina Sofía de Córdoba
Cordoba, Spain, 14004
Hospital Clínico Universitario San Cecilio
Granada, Spain, 18012
Hospital Universitario Virgen de las Nieves
Granada, Spain, 18014
Hospital General San Jorge
Huesca, Spain, 22004
Hospital Ciudad de Jaén
Jaen, Spain, 23007
Hospital Juan Canalejo
La Coruña, Spain, 15006
Hospital Ramón y Cajal
Madrid, Spain, 28034
Hospital de la Princesa
Madrid, Spain, 28006
Fundación Jiménez Díaz
Madrid, Spain, 28040
Hospital Gregorio Marañón
Madrid, Spain, 28007
Hospital La Paz
Madrid, Spain, 28046
Hospital Carlos Haya
Malaga, Spain, 29010
Hospital Comarcal Axarquía de Vélez
Malaga, Spain, 29740
Hospital Virgen de la Victoria
Malaga, Spain, 29010
Hospital General Universitario de Murcia
Murcia, Spain, 30003
Hospital General Universitario Morales Meseguer
Murcia, Spain, 30008
Hospital de Covadonga-Central de Asturias
Oviedo, Spain, 33006
Complejo Hospitalario de Pontevedra
Pontevedra, Spain, 36001
Hospital General de Segovia
Segovia, Spain, 40002
Hospital Doctor Peset
Valencia, Spain, 46017
Hospital La Fe de Valencia
Valencia, Spain, 46009
Hospital del Río Hortega
Valladolid, Spain, 47010
Hospital Virgen de la Concha
Zamora, Spain, 49021
Hospital Miguel Servet
Zaragoza, Spain, 50009
Sponsors and Collaborators
Clinical Trial Agency of HIV Study Group
Investigators
Study Chair: Juan Berenguer Berenguer, MD Hospital Gregorio Marañón
  More Information

No publications provided by Clinical Trial Agency of HIV Study Group

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
ClinicalTrials.gov Identifier: NCT00256828     History of Changes
Other Study ID Numbers: GESIDA-3903
Study First Received: November 21, 2005
Last Updated: October 15, 2007
Health Authority: Spain: Spanish Agency of Medicines

Keywords provided by Clinical Trial Agency of HIV Study Group:
HIV infection
Highly active antiretroviral therapy
Treatment Naive

Additional relevant MeSH terms:
Acquired Immunodeficiency Syndrome
HIV Infections
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Slow Virus Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Didanosine
Zidovudine
Lamivudine
Efavirenz
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Anti-HIV Agents

ClinicalTrials.gov processed this record on April 14, 2014