Clinical Trials Register

Summary
EudraCT Number:	2014-003142-27
Sponsor's Protocol Code Number:	RALAM
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:	2015-03-27
Trial 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

2014-003142-27

A.3

Full title of the trial

A pilot 24-week open-label, randomized, controlled clinical trial to assess the safety, tolerability and efficacy of dual therapy with Raltegravir/Lamivudine combination when replacing standard combination therapy in HIV-infected patients with prolonged virological suppression. RALAM Study

Ensayo clínico piloto de 24 semanas, abierto, aleatorizado, y controlado para evaluar la seguridad, tolerabilidad y eficacia de terapia dual con Raltegravir/Lamivudina, en sustitución de la terapia combinada estándar en pacientes infectados por VIH con supresión virológica prolongada. Estudio RALAM

A.3.1

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

A.3.2

Name or abbreviated title of the trial where available

RALAM Study

Estudio RALAM

A.4.1

Sponsor's protocol code number

RALAM

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	Fundació Clinic per a la Recerca Biomédica
B.1.3.4	Country	Spain
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	Merck Sharp & Dohme
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	CTU Clinic (Clinical Trial Unit)
B.5.2	Functional name of contact point	Jaime Camacho
B.5.3	Address:
B.5.3.1	Street Address	Villarroel 170
B.5.3.2	Town/ city	Barcelona
B.5.3.3	Post code	08036
B.5.3.4	Country	Spain
B.5.4	Telephone number	+349322754004386
B.5.5	Fax number	+34932279877
B.5.6	E-mail	jcamacho@clinic.ub.es

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	DUTREBIS (MK0518B)
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck Sharp & Dohme Limited
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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.3.4	Pharmaceutical form	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	Lamivudine
D.3.9.3	Other descriptive name	LAMIVUDINE HYDRATE
D.3.9.4	EV Substance Code	SUB131071
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	150
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Raltegravir
D.3.9.3	Other descriptive name	RALTEGRAVIR POTASSIUM
D.3.9.4	EV Substance Code	SUB25668
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
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 infection

Infección VIH cronica

E.1.1.1

Medical condition in easily understood language

Chronic HIV infection

Infeccion VIH cronica

E.1.1.2

Therapeutic area

Diseases [C] - Virus Diseases [C02]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Efficacy in virological suppression assessed with standard plasma HIV-1 RNA detection (limit of detection 37 copies/mL).

Evaluar la eficacia en la supresión virológica, mediante detección de HIV-1 RNA en plasma (límite de detección de 37 copias /ml).

E.2.2

Secondary objectives of the trial

Efficacy in virological suppression assessed with ultrasensitive HIV-1 RNA detection (limit of detection 1 copy/mL); Changes in peripheral mononuclear blood cells HIV-1 reservoir; Changes in metabolic parameters including fasting plasma lipids and insulin resistance (HOMA-IR); Changes in body fat composition and bone mineral density; Changes in plasma 25-OH vitamin D levels; Changes in estimated glomerular filtration rate (CKD-EPI) and urine beta-2-microglobulin
changes in immune activation markers including CD38 and HLA-DR; Changes in biomarkers of inflammation (IL-6, high sensitivity C-reactive protein) and biomarkers of mononuclear activation (SD-14, SD-163); Changes in sleep quality (Pittsburgh Sleep Quality Index); Changes in adherence in both treatment arms (Morisky-Green Test); overall tolerability

Evaluar la eficacia mediante detección ultrasensible de HIV-1 RNA (límite de detección de 1 copia/ml); Cambios en el reservorio de VIH-1 en células mononucleares sanguíneas periféricas; Cambios en parámetros metabólicos, incluyendo lípidos plasmáticos (en ayunas) y resistencia a la insulina (HOMA-IR); Cambios en la composición de la grasa corporal y en la densidad mineral ósea; Cambios en los niveles plasmáticos de Vitamina D 25-OH; Cambios en el índice de filtración glomerular estimado (CKD-EPI) y en la microglobulina-beta-2 urinaria; Cambios en marcadores de activación inmune, incluyendo CD38 y HLA-DR; Cambios en biomarcadores de la inflamación (IL-6, proteína C reactiva de alta sensibilidad) y biomarcadores de activación mononuclear (SD-14, SD-163); Cambios en la calidad del sueño (Índice de Calidad de Sueño de Pittsburgh, PSQI); Cambios en la adherencia al tratamiento en ambos grupos (Morisky-Green Test); Tolerabilidad general

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

a. Eligible patients will be males or females at least 18 years of age. Women of childbearing potential must have a negative pregnancy test within 10 days prior to randomization into the study.
b. Patients seropositive for HIV-1 using standard diagnostic criteria.
c. Patients virologicaly suppressed during at least 12 months prior to inclusion (viral load <50 copies/mL).
d. Patients on combination antiretroviral therapy (at least 2 antiretroviral drugs) for at least 12 months before being randomized in this study.
e. Patients who are clinically stable in the opinion of the investigator at study entry (clinical status and chronic medication must not have not been modified at least 14 days prior to randomization).
f. Patients who have signed informed consent to participate in the study

a. Los pacientes elegibles serán hombres o mujeres de al menos 18 años de edad. Las mujeres en edad de procrear deben contar con un test de embarazo negativo en los 10 días anteriores a su aleatorización en el estudio.
b. Pacientes seropositivos para VIH-1 mediante criterios diagnósticos habituales.
c. Pacientes en supresión virológica durante al menos los 12 meses anteriores a su inclusión (carga viral <50 copias/mL).
d. Pacientes en terapia antirretroviral combinada (al menos dos fármacos antirretrovirales) desde un mínimo de 12 meses previos a su aleatorización en este estudio.
e. Pacientes que estén clínicamente estables, en opinión del investigador, al ingresar en el estudio (la situación clínica y la medicación crónica no deben haberse modificado al menos durante los 14 días previos a la aleatorización).
f. Pacientes que hayan firmado el consentimiento informado para participar en el estudio.

E.4

Principal exclusion criteria

a. Pregnancy, lactation, or planned pregnancy during the study period.
b. Previous failure to an integrase inhibitor-containing regimen.
c. Previous failure to a 3TC or FTC-containing regimen.
d. Resistance mutations to 3TC or integrase inhibitor if any resistance test had been previously performed.
e. Any disease or history of disease which, in the opinion of the investigator, might confound the results of the study or pose additional risk to patient treatment.
f. Chronic hepatitis B.
g. Current therapy with RAL+3TC

a. Embarazo, lactancia o previsión de embarazo durante la duración del estudio.
b. Fracaso previo a regímenes que contengan inhibidor de la integrasa.
c. Fracaso previo a regímenes que contengan 3TC ó FTCP.
d. Mutaciones de resistencia a 3TC o al inhibidor de la integrasa, si se ha realizado algún test de resistencia previamente.
e. Cualquier enfermedad o antecedente de enfermedad que, en opinión del investigador, pueda confundir los resultados del estudio o plantear riesgos añadidos al tratamiento del paciente.
f. Hepatitis B crónica.
g. En tratamiento con RAL+3TC

E.5 End points

E.5.1

Primary end point(s)

The primary variable is the proportion of patients free of therapeutic failure at week 24. Therapeutic failure includes virological failure, change in treatment for any reason, consent withdrawal, loss to follow-up or death.
Virological failure is defined as two consecutive measurements of plasma viral load above 37 copies/ml (current detection limit in hospital lab) separated at least by 2 weeks during the assigned treatment, using the FDA snapshot method.

La variable principal es la proporción de pacientes libre de fracaso terapéutico a las 24 semanas. El fracaso terapéutico incluye fracaso virológico, cambio en el tratamiento cualquiera que sea la causa, retirada del consentimiento del estudio, pérdida de seguimiento o muerte.
El fracaso virológico se define como dos mediciones consecutivas de carga viral plasmática por encima de 37 copias/ml (límite actual de detección en el laboratorio del hospital).

E.5.1.1

Timepoint(s) of evaluation of this end point

week 24

24 semanas

E.5.2

Secondary end point(s)

1.Proportion of patients with viral load below 37copies/ml at 24 weeks
2.Proportion of patients with viral load below ultrasensitive HIV-1 RNA detection limit (limit of detection 1 copy/mL) at 24 weeks
3.Changes from baseline in peripheral mononuclear blood cells HIV-1 reservoir at 24 weeks;
4.Changes from baseline in metabolic parameters including fasting plasma lipids (cholesterol total, LDL, HDL and triglycerides) and insulin resistance (HOMA-IR) at 24 weeks;
5.Changes from baseline in body fat composition at 24 weeks;
6.Changes from baseline in lumbar and femoral bone mineral density at 24 weeks;
7.Changes from baseline in plasma 25-OH vitamin D levels at 24 weeks;
8.Changes from baseline in estimated glomerular filtration rate (CKD-EPI) and urine beta-2-microglobulin at 24 weeks;
9.Changes from baseline in immune activation markers including CD38 and HLA-DR at 24 weeks;
10.Changes from baseline in biomarkers of inflammation (IL-6, high sensitivity C-reactive protein) and biomarkers of mononuclear activation (SD-14, SD-163) at 24 weeks;
11.Changes from baseline in sleep quality (Pittsburgh Sleep Quality Index) at 24 weeks;
12.Incidence of adverse events in both treatment arms;
13.Proportion of patients discontinuing study treatment due to adverse events related to medication;
14.Proportion of patients with serious adverse events related to study medication;
15.Changes in treatment adherence during all the study duration (Morisky-Green test)

1.Proporción de pacientes con carga viral por debajo de 37 copias/ml a las 24 semanas.
2.Proporción de pacientes con carga viral por debajo del límite de detección ultrasensible de HIV-1 RNA (límite de detección de 1 copia/ml) a las 24 semanas.
3.Cambios en el reservorio de VIH-1 en células mononucleares sanguíneas periféricas a las 24 semanas.
4. Cambios en parámetros metabólicos, incluyendo lípidos plasmáticos en ayunas (colesterol total, LDL, HDL y triglicéridos); y resistencia a la insulina (HOMA-IR) a las 24 semanas.
5.Cambios en la composición de la grasa corporal a las 24 semanas.
6.Cambios en la densidad mineral ósea lumbar y femoral a las 24 semanas.
7.Cambios en los niveles plasmáticos de Vitamina D 25-OH a las 24 semanas.
8.Cambios en el índice de filtración glomerular estimado (CKD-EPI) y en la microglobulina-beta-2 urinaria a las 24 semanas.
9.Cambios en marcadores de activación inmune, incluyendo CD38 y HLA-DR a las 24 semanas.
10.Cambios en biomarcadores de la inflamación (IL-6, proteína C reactiva de alta sensibilidad) y biomarcadores de activación mononuclear (SD-14, SD-163) a las 24 semanas.
11.Cambios en la calidad del sueño (Índice de Calidad de Sueño de Pittsburgh, PSQI) a las 24 semanas.
12.Incidenca de acontecimientos adversos en los dos brazos de pacientes del estudio a las 24 semanas.
13.Proporción de pacientes que interrumpen el tratamiento del estudio debido a acontecimientos adversos relacionados con la medicación.

E.5.2.1

Timepoint(s) of evaluation of this end point

24 weeks

24 semanas.

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

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)

Yes

E.7.4

Therapeutic use (Phase IV)

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

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

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

LVLS

última visita último paciente

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

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:

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

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

normal treatment of that condition

tratamiento estándar de la enfermedad

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2015-07-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-11-18

P. End of Trial
P.	End of Trial Status	Completed

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