Clinical Trials Register

Summary
EudraCT Number:	2011-002107-15
Sponsor's Protocol Code Number:	Kirby-MARCH
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-01-31
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Spain - AEMPS

A.2

EudraCT number

2011-002107-15

A.3

Full title of the trial

Maraviroc Switch collaborative study
A randomised, open-label study to evaluate the efficacy and safety of maraviroc (MVC) as a switch for either nucleoside or nucleotide analogue reverse transcriptase inhibitors (N(t)RTI) or boosted protease inhibitors (PI/r) in HIV-1 infected individuals with stable, well-controlled plasma HIV-RNA while taking their first N(t)RTI + PI/r regimen of combination antiretroviral therapy (cART)

Ensayo clínico controlado, aleatorizado, abierto para evaluar la eficacia y seguridad de maraviroc en sustitución de los inhibidores análogos nucleósidos o nucleótidos (N(t)RTI) o de los inhibidores de la proteasa (IP) potenciados con ritonavir en pacientes con infección por VIH-1 y supresión virológica en su primer régimen con una combinación de N(t)RTI + IP/r

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Study to evaluate the efficacy and safety of maraviroc (MVC) as a switching treatment in HIV-1 infected patients in viral suppression while taking their first N(t)RTI + PI/r antiretroviral therapy.

Estudio apra evaluar la eficacia y la seguridad de maraviroc (MVC) como terapia de sustitución en pacientes infectados por el VIH-1 en supresión virológica en su primer régimen con una combinación de N(t)RTI + IP/r

A.3.2

Name or abbreviated title of the trial where available

MARCH

A.4.1

Sponsor's protocol code number

Kirby-MARCH

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Kirby Institute, University of New South Wa
B.1.3.4	Country	Australia
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Pfizer Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Kirby Institute, University of New South Wa
B.5.2	Functional name of contact point	Dr Sarah. L. Pett
B.5.3	Address:
B.5.3.1	Street Address	CC4 East Wing, UNSW Coogee Campus, 45 Beach Street
B.5.3.2	Town/ city	Coogee
B.5.3.3	Post code	2034
B.5.3.4	Country	Australia
B.5.4	Telephone number	61293850900
B.5.5	Fax number	61293850910
B.5.6	E-mail	spett@kirby.unsw.edu.au

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Celsentri
D.2.1.1.2	Name of the Marketing Authorisation holder	ViiV Healthcare UK Limited
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Celsentri
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	maraviroc
D.3.9.1	CAS number	192725170
D.3.9.2	Current sponsor code	H-C-368
D.3.9.3	Other descriptive name	CELSENTRI (maraviroc)
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	300 to 600
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Chronic HIV-1 infection

Infección crónica por el VIH-1

E.1.1.1

Medical condition in easily understood language

HIV infection

Infección por el VIH

E.1.1.2

Therapeutic area

Diseases [C] - Virus Diseases [C02]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10008919
E.1.2	Term	Chronic HIV infection
E.1.2	System Organ Class	10021881 - Infections and infestations

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of this study is to compare the virological efficacy of switching HIV-1 infected participants virologically suppressed on a combination of a nucleoside/nucleotide reverse transcriptase inhibitor backbone (nRTI) with a ritonavir-boosted protease inhibitor (PI/r) to remain on their current combination (arm 1 or control) or switch to a PI/r with maraviroc (arm 2) or nRTI plus maraviroc (arm 3) for 90 weeks of follow-up. The primary comparison of interest is the proportion of patients with HIV RNA <200 copies/mL 48 weeks after randomisation in the maraviroc arms vs. control arm.

Determinar la seguridad, eficacia y tolerabilidad del cambio a MVC en sustitución de 2N(t)RTI o IP/r en pacientes infectados con VIH-1 en supresión virológica con un régimen estable de 2N(t)RTI + IP/r.

E.2.2

Secondary objectives of the trial

A number of secondary outcomes will be assessed which are of relevance and interest in the assessment of the performance of the three study treatment regimens. These will include (but will not necessarily be limited to) virological, immunological, safety, clinical, metabolic, body composition changes, medication adherence and quality of life.

Los objetivos secundarios comprenden variables virológicas, inmunológicas, de seguridad, metabólicas, cambios de composición corporal, adherencia y calidad de vida.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. HIV-1 positive by licensed diagnostic test
2. Aged 18 years or older
3. HIV?1 RNA <200 copies/mL plasma for at least 24 weeks
4. Stable (>24 weeks) ART including two N(t)RTIs and a PI/r
5. No evidence of any primary HIV genotypic mutations in HIV reverse transcriptase or protease for all patients with available resistance testing results conducted prior to cART and/or during viral rebound/failure
6. Able to provide written informed consent

1. Infección por VIH-1 documentada en cualquier momento previo a la entrada en el estudio.
2. Edad >18 años.
3. CV plasmática <200 copias/mL durante al menos 24 semanas.
4. Tratamiento ART estable (>24 semanas), que incluya dos N(t)RTIs y un IP/r.
5. Ausencia de mutaciones genotípicas primarias a IPs o N(t)RTIs en aquellos pacientes con resultados de test de resistencia previos al inicio de cART y/o durante el fracaso virológico.
6. Otorguen el consentimiento informado por escrito.

E.4

Principal exclusion criteria

1. CXCR4 or CCR5/CXCR4 dual tropic HIV tropism or a non?reportable tropism result based on assessment using proviral DNA
2. Anticipated need to modify current cART regimen for toxicity management in the next 6 months
3. The following laboratory variables:
a) absolute neutrophil count (ANC) <750 cells/L
b) hemoglobin <8.0 g/dL
c) platelet count <50,000 cells/L
d) ALT and AST >5 x ULN
4. Pregnant or nursing mothers
5. Patients with active viral hepatitis B infection
6. Use of immunomodulators within 30 days prior to screening
7. Hypersensitivity to soy or peanuts
8. Intercurrent illness requiring hospitalisation

1. Tropismo viral dual CCR5/CXCR4 o CXCR4, o obtención de un resultado no valorable según determinaciones de ADN proviral.
2. Pacientes que puedan requerir de un cambio del cART actual en los siguientes 6 meses para el manejo de toxicidad.
3. Los siguientes criterios de laboratorio:
a. Recuento absoluto de neutrófilos <750 células/?L
b. Hemoglobina <8.0 g/dL
c. Recuento de plaquetas <50,000 células/?L
d. Transaminasas (AST, ALT) >5 x límite superior de normalidad (LSN)
4. Co-infección con hepatitis B aguda.
5. Mujeres embarazadas o en período de lactancia.
6. Utilización de fármacos contraindicados formalmente en la ficha técnica de cualquiera de los medicamentos en estudio.
7. Hipersensibilidad a la soja o cacahuetes.
8. Tratamiento agudo de infecciones graves o cualquier otra enfermedad médica grave (a juicio del Investigador Principal) que requieran de tratamiento sistémico y/u hospitalización.
9. Uso de inmunomoduladores (ej. corticosteroides sistémicos, interleukina 2 recombinante, interferón) dentro de los 30 días previos a la inclusión en el estudio.
10. Consumo actual de alcohol o de sustancias ilícitas que, según criterio del Investigador Principal, podrían interferir en el desarrollo y conducta del estudio.
11. Pacientes con dificultad para cumplir el seguimiento establecido por el protocolo del estudio.
12. Pacientes en prisión o detenidos.

E.5 End points

E.5.1

Primary end point(s)

The comparison of the switch arms to control arm of proportions of participants with HIV RNA <200 copies/mL 48 weeks after randomisation in the intention-to-treat (ITT) population.

Proporción de pacientes con CV<200 copias/ml entre las ramas de cambio y la rama control a las 48 semanas.

E.5.1.1

Timepoint(s) of evaluation of this end point

Week 48

Semana 48

E.5.2

Secondary end point(s)

A number of secondary endpoints will be examined at or through to week 48 in this protocol. These will include, but not be limited to the following:
Virologic endpoints
? Proportion of participants with plasma HIV RNA <50 copies/mL
? Time to virological failure (defined as plasma HIV RNA ?200 copies/mL on randomised therapy, on two occasions at least seven days apart)
? Time to loss of virological response, as defined by virological failure, permanent discontinuation of randomised treatment, new AIDS-defining illness, death or withdrawal from the study
? Changes from baseline in log plasma HIV RNA copies/mL
? Frequency of plasma HIV RNA blips (defined as a plasma viral load result >200 copies/mL on randomised therapy following a previous result <200 copies/mL, with a follow-up result <200 copies/mL at least seven days after the >200 copies/mL reading, in the absence of a change of any component of the ART regimen).
Immunologic and biomarker endpoints
? Changes from baseline in absolute and percentage CD4+ T cells
? Changes from baseline in selected soluble markers of immune activation/coagulation.
Clinical endpoints
? Rate of opportunistic disease (AIDS) or death
? Rates of Serious Non-AIDS-defining illness and Non-AIDS-related mortality.
Metabolic and body composition endpoints
? Changes from baseline in fasting lipids (TC, LDL-c, HDL-c and TG)
? Changes in absolute CVD risk assessment using the Framingham risk equation
? Changes from baseline in fasting glucose and insulin
? Rates of initiation or changes in existing lipid-lowering therapies
? Changes from baseline in anthropometric changes derived from Dual-energy X-ray absorptiometry (DXA) scanning of peripheral and central adipose tissue
? Changes from baseline in bone mineral density as measured by DXA
? Changes in 10-year fracture risk using the FRAX® algorithm
? Changes from baseline in markers of bone turnover.
Safety
? Changes from baseline in selected serum biochemical parameters, including changes in estimated glomerular filtration rate
? Proportions experiencing and types of SAEs
? Proportions experiencing, types and severity of AEs.
Adherence
? Self-reported adherence to randomised study medications.
Quality of Life
? Change from baseline health status scores as measured by the SF-12 health status.
Resistance endpoints
? Patterns of genotypic resistance at virological failure.

Variables virológicas
? Porcentaje de pacientes con CV<50 copias/mL.
? Tiempo hasta fracaso virológico (definido como CV>200 copias/mL en tratamiento asignado, en dos ocasiones consecutivas separadas al menos por siete días).
? Tiempo hasta pérdida de respuesta virológica, definido como fracaso virológico, discontinuación permanente del tratamiento asignado, nueva enfermedad definitoria de SIDA, muerte o retirada del estudio.
? Cambio respecto al basal del logaritmo de CV.
? Frecuencia de blips (definido como CV?200 copias/mL en tratamiento asignado tras un resultado previo de CV<200 copias/mL y con un resultado posterior de CV<200 copias/mL al menos siete días tras la obtención de la CV?200 copias/mL, en ausencia de cualquier cambio de fármacos antirretrovirales).

Variables inmunológicas y biomarcadores
? Cambio respecto al basal en el recuento absoluto y porcentaje de células T CD4+ y CD8+
? Cambio respecto al basal en determinados marcadores solubles de coagulación/activación inmune.
Variables clínicas
? Incidencia de enfermedades oportunistas (SIDA) o muerte
? Incidencia de enfermedades graves no definitorias de SIDA y tasa de mortalidad no relacionada con el SIDA.

Variables metabólicas y de composición corporal
? Cambio respecto al basal de los niveles de lípidos en ayunas (colesterol total, colesterol LDL, colesterol HDL y triglicéridos).
? Cambios en la evaluación de riesgo absoluto de enfermedad cardiovascular según la Escala de Framingham.
? Cambio respecto al basal de los niveles de glucosa e insulina en ayunas.
? Porcetanje de pacientes con inicio o cambios en el tratamiento con agentes hipo-lipemiantes.
? Cambio respecto al basal en cambios antropométricos de tejido adiposo periférico y central mediante DEXA (densitometría de rayos X con doble nivel de energía).
? Cambio respecto al basal en la distribución de la grasa corporal y densidad mineral ósea mediante DEXA.
? Cambios en el riesgo de fracturas a diez años en base al algoritmo FRAX®.
? Cambio respecto al basal de marcadores de recambio óseo.

Seguridad
? Cambio respecto al basal de determinados parámetros bioquímicos en suero, incluidos los cambios en el índice de filtrado glomerular renal (FGR).
? Proporción de pacientes con acontecimientos adversos graves (SAEs) y tipos de SAEs.
? Proporción de pacientes con acontecimientos adversos (AA) y tipos y gravedad de AAs.

Adherencia
? Adherencia a los tratamientos asignados según adherencia informada por los propios pacientes.

Calidad de vida
? Cambio respecto al basal de calidad de vida según el cuestionario SF-12.

Variables de resistencia
? Patrones de resistencia genotípica durante el fracaso virológico.

E.5.2.1

Timepoint(s) of evaluation of this end point

Week 48

Semana 48

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

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

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Argentina

Australia

Canada

Chile

France

Germany

Ireland

Israel

Mexico

Peru

Singapore

Spain

United Kingdom

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

The trial will be completed when all patients have attended for 96 weeks of follow-up, unless the DSMB have ceased the study early due to safety or tolerability concerns.

El estudio finalizará una vez todos los pacientes completen la semana 96 de seguimiento a no ser que el DSMB concluya finalizarlo de manera prematura por problemas de seguridad o eficacia.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

544

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception