Clinical Trials Register

Summary
EudraCT Number:	2016-002722-36
Sponsor's Protocol Code Number:	RAGTIME
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2017-01-04
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

2016-002722-36

A.3

Full title of the trial

Randomized, double-blind, placebo-controlled clinical trial to evaluate the effect of Raltegravir intensification (1.200 mg QD) on the gut microbiota of chronically HIV-1 infected subject over time: THE RAGTIME STUDY

Ensayo clínico aleatorizado, doble ciego, controlado con placebo para evaluar el efecto en el tiempo de la intensificación con raltegravir (1.200 mg QD) en la composición de la microbiota intestinal en sujetos con infección crónica por VIH-1: Estudio Ragtime

A.3.1

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

Clinical trial to evaluate the effect of Raltegravir intensification (1.200 mg QD) on the gut microbiota of chronically HIV-1 infected subject over time

Ensayo clínico para evaluar el efecto en el tiempo de la intensificación con raltegravir (1.200 mg QD) en la composición de la microbiota intestinal en sujetos con infección crónica por VIH-1

A.4.1

Sponsor's protocol code number

RAGTIME

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 LLUITA CONTRA LA SIDA
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	Fundació Lluita contra la SIDA
B.4.2	Country	Spain
B.4.1	Name of organisation providing support	Merck Sharp And Dohme
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Fundació Lluita contra la SIDA
B.5.2	Functional name of contact point	CRA
B.5.3	Address:
B.5.3.1	Street Address	Ctra. Canyet sn
B.5.3.2	Town/ city	Badalona/Barcelona
B.5.3.3	Post code	08916
B.5.3.4	Country	Spain
B.5.4	Telephone number	+3493497 84 14
B.5.5	Fax number	+3493465 76 02
B.5.6	E-mail	jtoro@fls-rs.com

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	No
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	Raltegravir
D.3.2	Product code	MK-0518
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	RALTEGRAVIR
D.3.9.1	CAS number	518048-05-0
D.3.9.4	EV Substance Code	SUB25667
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	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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

HIV-1

VIH-1

E.1.1.1

Medical condition in easily understood language

Human inmunodeficiency virus

Virus de inmunodeficiencia humana

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	19.0
E.1.2	Level	LLT
E.1.2	Classification code	10068341
E.1.2	Term	HIV-1 infection
E.1.2	System Organ Class	100000004862

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the ability of raltegravir intensification to increase gut microbiome richness and modify the gut microbiome composition of people living with HIV receiving stable ART.

Evaluar la capacidad de la intensificación con raltegravir en aumentar la riqueza del microbioma intestinal y modificar la composición de éste en las personas que viven con la infección por VIH y que reciben un tratamiento antirretroviral estable.

E.2.2

Secondary objectives of the trial

To correlate changes in the gut microbiota composition and richness with markers of inflammation, coagulation, enterocyte damage, bacterial translocation and T-cell maturation, activation, exhaustion and senescence during raltegravir intensification.

Correlacionar los cambios en la composición y riqueza de la microbiota intestinal durante la intensificación con raltegravir con marcadores de inflamación, coagulación, daño enterocitario, translocación bacteriana y maduración de células T, activación y agotamiento y senescencia.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Age ≥18 years old
2. Documented HIV infection
3. Stable antiretroviral treatment including PIi/r or NNRTIi-based 3 drugs ART for at least 6 months.
4. Plasma HIV-1 RNA load <50 copies/mL for at least 12 months.
5. Signed Informed Consent

1. Edad ≥ 18 años
2. Infección documentada del VIH
3. Tratamiento antirretroviral estable con 3 antirretrovirales incluyendo PI/r o NNRTI durante al menos 6 meses.
4. Carga viral <50 copias/ml durante al menos 12 meses.
5. Consentimiento informado firmado

E.4

Principal exclusion criteria

1. PI/r monoterapy
2. INSTI therapy during the previous 6 months
3. Evidence of previous INSTI resistance
4. Creatine clearance <50 mL/min
5. Child- Pugh B or C
6. History of active uncontrolled GI disorders or diseases including:
6.1. Major surgery of the GI tract, with the exception of cholecystectomy and appendectomy, in the previous 5 years.
6.2. Any major bowel resection at any time
6.3. Any chronic digestive disease such as peptic ulcer, Crohn’s disease, ulcerative colitis, coeliac disease, confirmed intolerance to lactose or indeterminate colitis.
6.4. Persistent infectious gastroenteritis, colitis or gastritis; persistent or chronic diarrhea of unknown etiology; Clostridium difficile infection (recurrent) or Helicobacter pylori infection (untreated);
6.5. Irritable bowel syndrome (moderate-severe)
6.6. Chronic constipation
6.7. Active proctitis
7. Antibiotic therapy within the previous 2 months
8. In women, pregnancy or breastfeeding

1. IP/r en monoterapia
En tratamiento con INSTI durante los 6 meses previos
3. Evidencia de resistencia previa a INSTI
4. Aclaramiento de creatinina <50 mL/mín
5. Child-Pugh B o C
6. Historia de alteraciones o enfermedades gastrointestinales activas incluyendo:

6.1. Cirugía mayor del tracto GI, con la excepción de colecistectomía y apendicetomía, en los últimos 5 años.
6.2. Cualquier resección intestinal importante.
6.3. Cualquier enfermedad digestiva crónica como úlcera péptica, enfermedad de Crohn, colitis ulcerosa, enfermedad celíaca, intolerancia a la lactosa confirmada o colitis indeterminada.
6.4. Gastroenteritis infecciosa persistente, colitis o gastritis; diarrea persistente crónica de etiología desconocida; infección por Clostridium difficile (recurrente) o infección por Helicobacter pylori (no tratada)
6.5. Síndrome del intestino irritable (moderado- severo)
6.6. Estreñimiento crónico
6.7. Proctitis activa

7. Tratamiento con antibiótico en los 2 meses previos.
8. Mujeres embarazada o en periodo de lactancia

E.5 End points

E.5.1

Primary end point(s)

Increase in bacterial richness (observed species).

Aumento de la riqueza bacteriana (especies observadas).

E.5.1.1

Timepoint(s) of evaluation of this end point

At week 48, relative to baseline (week 0).

En la semana 48, en relación con el basal (semana 0).

E.5.2

Secondary end point(s)

•Longitudinal changes in:
-Gut bacterial composition
-Gut bacterial function
-Other estimators of richness and diversity: Chao1, ACE, Shannon, 1/Simpson.
•Association of the gut microbiome composition and richness with:
-Inflammation: IL-6, IP-10
-Coagulation: D-Dimer
-Enterocyte damage: Intestinal Fatty Acid Binding Protein (I-FABP)
-Bacterial translocation and monocyte activation: LPS-binding protein (LBP), soluble CD14.
-Maturation, activation, exhaustion and immune senescence in CD4+ and CD8+ T-cells: CD3+, CD4+, CD8+, CD45RA, CCR7, CD28, CD27, HLA-DR, CD38, PD-1, CD57.
-CD4 and CD8+ counts
-CD4+/CD8+ ratio

• Cambios longitudinales en:
- Composición bacteriana intestinal
- Función bacteriana intestinal
- Otros estimadores de riqueza y diversidad: Chao1, ACE, Shannon, 1 / Simpson.
• Asociación de la composición microbioma intestinal y la riqueza con:
- Inflamación: IL-6, IP-10
- Coagulación: D-Dimer
- Daños Enterocito: proteína de unión intestinal de ácidos grasos (I-FABP)
- Translocación Bacteriana y activación de monocitos: proteína de unión a LPS (LBP), CD14 soluble.
- Maduración, activación, agotamiento y senescencia inmunitaria en T CD4 + y CD8 +: CD3 +, CD4 +, CD8 +, CD45RA, CCR7, CD28, CD27, HLA-DR, CD38, PD-1, CD57.
- CD4 y CD8 +
- % CD4 + / CD8 +

E.5.2.1

Timepoint(s) of evaluation of this end point

Baseline, weeks 12, 24, 48

Basal y semanas 12, 24, 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

E.6.4

Safety

E.6.5

Efficacy

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

Yes

E.6.13.1

Other scope of the trial description

Evaluate the ability of raltegravir intensification to increase gut microbiome richness and modify the gut microbiome composition

Evaluar la capacidad de la intensificación con raltegravir para aumentar la riqueza del microbioma intestinal y modificar su composición

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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)

E.8.2.2

Placebo

Yes

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

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 del 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)

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

F.3.3.2

Women of child-bearing potential using contraception

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)

Continue to previous antiretroviral treatment

Continuar con el tratamiento antirretroviral previo al estudio

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

2017-03-29

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-02-24

P. End of Trial
P.	End of Trial Status	Ongoing

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