| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| HIV infection |
| Infección VIH |
|
| E.1.1.1 | Medical condition in easily understood language |
| HIV infection |
| Infección VIH |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To demonstrate the clinical benefit of the adjunction of Maraviroc to a combination of antiretroviral therapy in naïve and late diagnosed HIV-1 infected patients.
The clinical benefit is the reduction of the occurrence of a composite outcome consisting of new AIDS-defining event (ADE), Non B or C events, serious non-AIDS events, IRIS and death. |
Demostrar el beneficio clínico de añadir Maraviroc a un tratamiento antirretroviral combinado en pacientes naïve infectados por el VIH-1 y diagnosticados tardíamente.
El beneficio clínico consiste en la reducción de la aparición de un resultado compuesto formado por un nuevo acontecimiento definitorio de SIDA (ADS), acontecimientos no B no C de SIDA, acontecimientos graves no definitorios de SIDA, SIRI y muerte. |
|
| E.2.2 | Secondary objectives of the trial |
- To compare Maraviroc to Placebo arm for each component of the primary composite end point and other major outcomes;
- Impact of CCR5 tropism on primary and major secondary end points;
- Immunologic evaluation;
- Virological evaluation;
- Pharmacology substudy;
- Safety of the strategy;
- Cost-effectiveness study. |
- Comparar la rama de Maraviroc con la de placebo para cada uno de los componentes de la variable principal compuesta y otros resultados importantes;
- Impacto del tropismo del CCR5 sobre la variable principal y las principales variables secundarias;
- Evaluación inmunológica;
- Evaluación virológica;
- Subestudio de farmacología;
- Seguridad de la estrategia;
- Estudio de la relación coste-eficacia. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| Confirmed HIV-1 infection (positive ELISA and Western Blot tests or positive ELISA and Immunoblot or positive ELISA and positive viral load); ? Adult patients (age >= 18 years); ? CD4+ T lymphocytes <= 200/mm3 and/or previous AIDS-defining-illness at W-2 or W-4; ? Patient naïve from any antiretroviral; ? In women, use of a contraceptive method, and lack of actual pregnancy; ? Patients with a coverage from social health; ? After informed consent. |
| ? Infección por VIH-1 confirmada (pruebas de ELISA y Western-Blot positivas o ELISA e Inmunoblot positivos o ELISA positivo y carga viral positiva); ? Pacientes adultos (edad ? 18 años); ? Linfocitos T CD4+ ? 200/mm3 y/o enfermedad definitoria de SIDA previa en la S-2 o S-4; ? Paciente naïve para cualquier antirretroviral; ? En mujeres, uso de un método anticonceptivo y ausencia de embarazo; ? Pacientes con cobertura de la seguridad social; ? Haber firmado el consentimiento informado. |
|
| E.4 | Principal exclusion criteria |
? Current pregnancy, lack of contraceptive method, breast-feeding; ? Current active tuberculosis (either suspected, diagnosed); ? Ongoing malignancies except cutaneous Kaposi?s sarcoma. Patients with a previous cancer considered as cured for at least 6 months could be included in the study; ? Current or previous severe cardiac failurea, chronic respiratory diseaseb, renalc or liver insufficiency; any life-threatening organ failure; ? Cognitive impairment, psychiatric disorders, severe depressive affects, inadapted behavior; ? Use of cytostatic drugs, immunosuppressive agents, steroids. Treatment with steroids can be authorized if they are given for less than two months as adjuvant treatment for opportunistic infections; ? PMN < 750/mm3, platelets < 50,000/mm3, haemoglobin < 10 g/dL; ASAT, ALAT or bilirubin > 2.5 ULN; lipase > 2 ULN, serum creatinine > 1.5 ULN; proteinuria > 1g/L; INR abnormal (Note: normal INR values are included between 0.8 and 1.3)d; ? Current or previous, during the 3 last months, use of immunomodulatory agents (G-CSF, IL-2, GM-CSF, interferons, pentoxifylline);
? Hypersensitivity to peanut and /or soy products.
a: if a severe cardiac failure is suspected, an echocardiography should be performed (ejection fraction < 45% should not be included in the trial).
b: Patients having a Chronic Obstructive Pulmonary Disease can not be included in the trial.
c: Renal insufficiency defined by creatinine clearance < 60/mL.
d: Patients taking anticoagulant can be included in the trial. |
Presencia de embarazo, no utilización de un método anticonceptivo, lactancia materna en este momento; ? Tuberculosis activa en este momento (tanto sospechada como diagnosticada); ? Cualquier proceso canceroso en curso excepto el sarcoma cutáneo de Kaposi. En el estudio se podrá incluir a los pacientes que hayan pasado un proceso canceroso y que desde al menos 6 meses antes se considere que están curados; ? Insuficiencia cardíaca grave actual o previaa, enfermedad respiratoria crónicab, insuficiencia renalc o hepática, fracaso de cualquier órgano que ponga en peligro la vida del paciente; ? Alteración cognitiva, trastornos psiquiátricos, estados depresivos graves, comportamiento inadaptado;
? Uso de fármacos citostáticos, inmunosupresores o corticoides;; el tratamiento con esteroides puede ser autorizado si la duración de éste es de menos de dos meses y se trata de un tratamiento adyuvante a las infecciones oportunistas.
? PMN < 750/mm3, plaquetas < 50.000/mm3, hemoglobina < 10 g/dl; ASAT, ALAT o bilirrubina > 2,5 LSN; lipasa > 2 LSN, creatinina sérica > 1,5 LSN; proteinuria > 1g/l; INR anormal (Nota: los valores normales de INR están comprendidos entre 0,8 y 1,3)d; ? Uso actual o previo, durante al menos 3 meses, de fármacos inmunomoduladores (G-CSF; IL-2, GM-CSF, interferones, pentoxifilina);
? Hipersensibilidad a los cacahuetes y/o a los productos de soja.
a: Si se sospecha la presencia de una insuficiencia cardíaca grave, se deberá realizar una ecocardiografía (no se debe incluir en el ensayo a los pacientes con una fracción de eyección < 45%).
b: No se puede incluir en el ensayo a los pacientes con enfermedad pulmonar obstructiva crónica.
c: La insuficiencia renal viene definida por el aclaramiento de creatinina < 60/ml.
d: Los pacientes que toman anticoagulantes se pueden incluir en el ensayo. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
o New ADE (opportunistic events consistent with the 1993 CDC expanded surveillance definition plus additional events associated with immunosuppression in the patient population targeted for enrolment) (APPENDIX XI).
o Non B or C:
? Aspergillosis, invasive,
? Bartonellosis, includes bacillary angiomatosis and peliosis hepatis,
? Chagas disease (American trypanosomiasis) of the central nervous system (CNS),
? Leishmaniasis, visceral (kala-azar),
? Lymphoma, Hodgkin's,
? Lymphoma, non-Hodgkin's, other cell type,
? Microsporidiosis, chronic intestinal (> 1 month's duration),
? Nocardiosis,
? Penicillium marneffei, extrapulmonary,
? Pneumocystis jiroveci, extrapulmonary,
? Rhodococcus equi disease,
? Severe infections: defined by sepsis with bacteremia requiring overnight hospitalisation, or pneumonia requiring overnight hospitalisation.
o Serious non-AIDS events (APPENDIX XII):
? Cardiovascular disease (CVD): myocardial infarction, stroke, coronary revascularization,
? Chronic end stage renal disease (ESRD),
? Liver failure,
? Non-AIDS-defining cancers except basal and squamous cell skin cancers,
? IRIS,
o All causes of mortality (related or not to AIDS). |
?o Nuevo ADS (acontecimientos oportunistas que concuerden con la definición de casos para la vigilancia ampliada de los CDC de 1993 más acontecimientos adicionales asociados con la inmunodepresión en la población fijada como objetivo del estudio) (APENDICE XI).
?o No B o C:
o? Aspergilosis invasiva,
o? Bartonelosis, incluyendo angiomatosis bacilar y peliosis hepática,
o? Enfermedad de Chagas (tripanosomiasis americana) del sistema nervioso central (SNC),
o? Leishmaniasis visceral (kala-azar),
o? Linfoma de Hodgkin
o? Linfoma no Hodgkin, otro tipo celular,
o? Microsporidiosis intestinal crónica (> 1 mes de duración),
o? Nocardiosis,
o? Peniciliosis extrapulmonar por Penicillium marneffei,
o? Infección extrapulmonar por Pneumocystis jiroveci,
o? Enfermedad por rhodococcus equi,
o? Infecciones graves: definidas por sepsis con bacteriemia que requiere hospitalización inmediata o neumonía que requiere hospitalización inmediata.
?o Acontecimientos graves no definitorios de SIDA (APENDICE XII):
o? Enfermedad cardiovascular (ECV): infarto de miocardio, embolia, revascularización coronaria,
o? Enfermedad renal crónica en etapa terminal (ERET),
o? Insuficiencia hepática,
o? Cánceres no definitorios de SIDA excepto los cánceres cutáneos de células basales y escamosas,
o? SIRI,
?o Todas las causas de mortalidad (relacionadas o no con el SIDA). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Until week 72 |
| Hasta semana 72 |
|
| E.5.2 | Secondary end point(s) |
o Clinical Events:
New ADE (opportunistic events consistent with the 1993 CDC expanded surveillance definition plus additional events associated with immunosuppression in the patient population targeted for enrolment),Non B or C
-Aspergillosis, invasive,
-Bartonellosis, includes bacillary angiomatosis and peliosis hepatis,
-Chagas disease (American trypanosomiasis) of the CNS,
-Leishmaniasis, visceral (kala-azar),
-Lymphoma, Hodgkin's,
-Lymphoma, non-Hodgkin's, other cell type,
-Microsporidiosis, chronic intestinal (> 1 month's duration),
-Nocardiosis,
-Penicillium marneffei, extrapulmonary,
-Pneumocystis jiroveci, extrapulmonary,
-Rhodococcus equi disease,
-Severe infections: defined by sepsis with bacteremia requiring overnight hospitalisation, or pneumonia requiring overnight hospitalisation.
Serious non-AIDS events,
-CVD: myocardial infarction, stroke, coronary revascularization,
-Chronic ESRD,
-Liver failure,
-Non-AIDS-defining cancers except basal and squamous cell skin cancers,
-IRIS,
Grade 4 events (APPENDIX XIII)
All causes of mortality (related or not to AIDS).
o Immunological end points (APPENDIX X):
Absolute number of T CD4+ lymphocytes at W4, W8, W12, W24, W36, W48, W60, W72,
Percentage of patients with > 200 CD4+ T lymphocytes at W4, W8, W12, W24, W36, W48, W60, W72,
Phenotypic analysis of CD4+ T lymphocytes, CD8+ T lymphocytes (naïve, central memory cells, and cytotoxic cells) and evolution of markers of immune activation (expression of HLA-DR and CD38 on CD4 and CD8 T cells) at W0, W8, W24, W60 (substudy),
Seric markers of immune activation (inflammation): Hs-CRP, fibrinogen, IL-6, IL-1-beta, IFN-alpha, d-dimers, SAA and sCD14 at W0, W8, W24, W60 (substudy),
Density of CCR5 and CXCR4 expression at W0, W8, W24 (substudy),
Expression of homing receptors on CD4 T lymphocytes (% of cells CD4+a4b7+CCR9+) at W0, W8, W24 (substudy),
Evaluation of HIV-1 and recall-antigen specific immune responses by Intra-Cellular Staining (ICS) at W0, W24 (substudy).
o Virological end points (APPENDIX IX):
Percentage of patients with a plasma HIV-1 RNA < 400 copies/mL and <50 copies/mL at W0, W4, W8, W12, W24, W36, W48, W60, W72,
Plasma HIV-1 RNA at W-4, W0, W4, W8, W12, W24, W36, W48, W60, W72,
Tropism testing performed by Tropisme Test Toulouse at baseline (W0) on plasma HIV-1 RNA and in patients with detectable plasma HIV-1 RNA during the study (on the first sample with HIV-1 RNA > 1000 copies/ml after week 24),
Resistance testing performed in patients with detectable plasma HIV-1 RNA during the study (on the second sample with HIV-1 RNA > 400 copies/ml after week 24),
Virological study (for all patients enrolled in France):
HIV-1 DNA in PBMC (peripheral blood mononuclear cells) at W0, W24, W72 (whole blood samples),
Tropism testing by genotypic analysis of the V3 loop to investigate (1) the correlation with virology response at W0 on plasma HIV RNA, and (2) the tropism evolution in patients with undetectable viral load at W0, W24, W72 on HIV-1 DNA.
Seminal compartment sub-study (for 20 patients in each group):
? HIV viral load will be determined at W0, W24,
? HIV tropism will be determined at W0, W24.
o Pharmacokinetic (PK) end points (APPENDIX VIII)
PK analysis:
Determinations of MVC trough plasma concentration of MVC (Cmin; 12 ? 2 hours after the last drug intake) at W4 and W24 in all patients randomized in Group 2* using UPLC-MS/MS,
? Distributions of MVC Cmin by dosing regimen and according to the associated PI Ritonavir-boosted or EFV,
? Between and within patients variability of MVC Cmin,
Substudy in 25 patients in each group to calculate the:
? Steady-state plasma area under curve (AUC) of MVC at W4 based on the determination of 0h, 1h, 3h, 6h, 8h, 12h post dose concentrations of MVC,
? Average of MVC concentration at W4 (Cave = AUC/12h),
? Free fraction AUC (unbound to plasma protein) of MVC at W4,
Determination of MVC Cmin for study discontinuations (before the end point) (adverse events, virological failure, etc.),
Determination of MVC seminal at W24 in a subgroup of 20 patients from Group 2, |
Acontecimientos clínicos:
oNuevo ADS (acontecimientos oportunistas que concuerden con la definición de casos para la vigilancia ampliada de los CDC de 1993 más acontecimientos adicionales asociados con la inmunodepresión en la población fijada como objetivo del estudio),
oNo B o C
-Aspergilosis invasiva,
-Bartonelosis, incluyendo angiomatosis bacilar y peliosis hepática,
-Enfermedad de Chagas (tripanosomiasis americana) del SNC,
-Leishmaniasis visceral (kala-azar),
-Linfoma de Hodgkin,
-Linfoma no Hodgkin, otro tipo celular,
-Microsporidiosis intestinal crónica (> 1 mes de duración),
-Nocardiosis,
-Peniciliosis extrapulmonar por Penicillium marneffei,
-Infección extrapulmonar por Pneumocystis jiroveci,
-Enfermedad por rhodococcus equi,
-Infecciones graves: definidas por sepsis con bacteriemia que requiere hospitalización inmediata o neumonía que requiere hospitalización inmediata.
oAcontecimientos graves no definitorios de SIDA,
-ECV: infarto de miocardio, embolia, revascularización coronaria,
-ERET,
-Insuficiencia hepática,
-Cánceres no definitorios de SIDA excepto los cánceres cutáneos de células basales y escamosas,
-SIRI,
?Acontecimientos de grado 4 (APENDICE XIII)
?Todas las causas de mortalidad (relacionadas o no con el SIDA). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| During all the trial |
| Durante todo el ensayo |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 25 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 75 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Until last patient included reach W72 |
| Ultimo paciente incluido alcance Semana 72 |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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