| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 assess the efficacy of a switch to DTG/3TC for maintenance of virologic suppression at 48 weeks in persons with past confirmed or suspected 3TC resistance, when proviral DNA population sequencing does not detect 3TC resistance-associated mutations at baseline. |
| Evaluar la eficacia del switch a DTG/3TC para el mantenimiento de la supresión virológica a 48 semanas en personas con resistencia confirmada o sospechada a 3TC, en los que la secuenciación poblacional de ADN proviral no detecta mutaciones de resistencia a 3TC al inicio del estudio |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate other estimations of virological control at weeks 48 and 96.
- To assess viral resistance in persons experiencing VF
- To evaluate factors associated with VF.
-To assess the impact of baseline archived minority 3TC resistance-associated mutations in viral control (in cases of VF and transient viral rebounds [VL≥50copies/mL preceded and followed by VL<50 copies / Ml).
- To evaluate the dynamics of archived minority 3TC resistance-associated mutations after switching to DTG/3TC at 96 weeks.
- To evaluate the immune effects of switch to DTG/3TC
- To evaluate the safety and tolerability of DTG/3TC in this study |
- Evaluar otras estimaciones del control virológico a semanas 48 y 96.
- Evaluar otras estimaciones del control virológico a semanas 48 y 96.
- Evaluar factores asociados al FV
- Evaluar el impacto de mutaciones de resistencia asociadas a 3TC archivadas minoritarias basales en el control virológico (en casos de FV y repuntes virológicos transitorios [CV≥50copias/mL precedida y seguida de CV<50 copias/mL]).
- Evaluar las dinámicas de las mutaciones de resistencia minoritarias archivadas a 3TC tras el switch a DTG/3TC a semana 96.
- Evaluar los efectos en la inmunidad del switch a DTG/3TC.
- Evaluar la seguridad y tolerabilidad de DTG/3TC en este estudio |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
a. Adults ( 18 years old) with HIV-1 infection able to understand and give informed written consent.
b. Stable ART in the 12 weeks prior to screening visit.
- Only switch for tolerability/convenience/access reasons to generic drugs or switch from ritonavir to cobicistat or TDF to TAF would be allowed in the 12-week window and as long as the components of the regimen are unchanged.
c. Viral load <50 copies/mL at screening and in the year prior to study entry.
- A blip (50-500 copies/ml) would be allowed within 48 weeks prior to inclusion in the study, if preceded and followed by an undetectable VL determination.
d. CD4 count > 200 cel/μL at screening.
e. History of 3TC resistance: either confirmed historical 3TC resistance (historical RNA Sanger or RNA NGS>20% threshold genotype with M184V/I mutation) OR suspected historical 3TC resistance.
- Suspicion of past 3TC resistance is defined as any of the following:
i. Previous treatment with only 2 NRTIs (1 of them being emtricitabine or 3TC [XTC]).
ii. Two consecutive VL > 200 cp/mL while on treatment including XTC.
iii. One VL > 200 cp/mL while on treatment including XTC PLUS change of ART as consequence of that elevated VL. |
a. Adultos ( 18 años) con infección por VIH-1 con capacidad para entender y dar consentimiento informado por escrito.
b. TAR estable en las 12 semanas anteriores a la visita de screening.
- Sólo se admitirán cambios debido a motivos de tolerabilidad/conveniencia/acceso a genéricos o cambios de ritonavir a cobicistat o TDF a TAF en la ventana de 12 semanas, siempre y cuando los componentes del régimen permanezcan inalterados.
c. CV <50 copias/mL en el screening y en el año anterior a la participación en el ensayo
- Se permitirá un blip (CV 50-500 copias/ml) en las 48 semanas anteriores a la inclusión en el estudio, sólo si precedido y seguido de una CV indetectable.
d. Cifra de CD4+> 200 cél/μL en la visita de screening.
e. Historia de resistencia a 3TC: resistencia histórica confirmada a 3TC (genotipo histórico ARN o ARN NGS >20% con la mutación M184V/I) O resistencia histórica sospechada a 3TC.
- Resistencia sospechada a 3TC previa se define como cualquiera de las siguientes:
i. Tratamiento previo con sólo dos ITIAN (1 de ellos siendo emtricitabina o 3TC [XTC]).
ii. Dos CV > 200 cp/mL consecutivos bajo tratamiento que incluyese XTC.
iii. Una CV> 200 cp/mL bajo tratamiento que incluyese XTC Y cambio de TAR a consecuencia de dicha elevación de CV. |
|
| E.4 | Principal exclusion criteria |
a. Participants with M184V/I or K65R in screening visit proviral DNA Sanger
genotype.
b. Prior virologic failure (VF) under integrase inhibitor (INSTI)- based regimen.
defined as two consecutive VL > 200 copies/mL while receiving INSTI
regardless of genotypic test results
c. INSTI resistance mutations in historical RNA genotype.
d. Positive Surface Hepatitis B Ag (HBAgS) OR negative HBAgS and negative
hepatitis B surface antibody (anti-HBs) with positive anti-core antibody (anti-
HBc) and positive HBV DNA.
e. Pregnant, breastfeeding women, women with a positive pregnancy test at the
time of screening, sexually active fertile women wishing to conceive or unwilling
to commit to contraceptive methods (see Appendix 1 for the accepted list of the
highly effective methods for avoiding pregnancy), for the duration of the study
and until 4 weeks after the last dose of study medication. All women are
considered fertile unless they have undergone a sterilizing surgery or are over
the age of 50 with spontaneous amenorrhea for over 12 months prior to study
entry.
f. Patients with active opportunistic infections or cancer requiring intravenous
treatment and/or chemotherapy at screening.
g. Any comorbidities or treatment with experimental drugs that according to the
investigator could bias study results or entail additional risks for the participant.
h. Participants receiving other medications that according to study drug label are
contraindicated.
i. Severe hepatic impairment (Class C) as determined by Child-Pugh
classification.
j. Alanine aminotransferase (ALT) over 5 times the upper limit of normal (ULN) or
ALT over 3xULN and bilirubin over 1.5xULN.
k. Unstable liver disease (as defined by the presence of ascites, encephalopathy,
coagulopathy, hypoalbuminemia, oesophageal or gastric varices, or persistent
jaundice), cirrhosis, known biliary abnormalities (apart from hyperbilirubinemia
or jaundice due to Gilbert's syndrome or asymptomatic gallstones);
l. Creatinine clearance of <30 mL/min/1.73m2 via CKD-EPI method.
m. Any verified Grade 4 laboratory abnormality that to the investigators criteria
would affect the safety of the participant if included in the study.
n. History or presence of allergy to dolutegravir or lamivudine. |
a. Participantes con M184V/I o K65R en la visita de screening en genotipo Sanger de ADN proviral.
b. FV previo bajo tratamiento basado en un inhibidor de la integrasa, definido como 2 CV consecutivas > 200 copias/mL mientras recibía el INI, independientemente del resultado del test genotípico.
c. Mutaciones de resistencia a INI en genotipos ARN históricos.
d. Antígeno de superficie positivo para el virus de la Hepatitis B (HBAgS) O HBAgS negativo y anticuerpo de superficie para la hepatitis B (anti-HBs) negativo con anticuerpo anti-core positivo (anti-HBc) y ADN HBV positivo.
e. Mujeres embarazadas, lactantes, mujeres con un test de embarazo positivo en la visita de screening, mujeres fértiles sexualmente activas con deseo de concebir o que no estén dispuestas a comprometerse al uso de métodos contraceptivos (ver Apéndice 1 para el listado aceptado de métodos altamente efectivos para evitar el embarazo), durante todo el periodo de estudio y hasta 4 semanas después de la última dosis de medicación del estudio. Todas las mujeres son consideradas fértiles a no ser que se hayan sometido a cirugía esterilizante o sean mayores de 50 años con amenorrea espontánea durante más de 12 meses previo a entrar al estudio.
f. Pacientes con infecciones oportunistas activas o cáncer que requiera tratamiento intravenoso y/o quimioterapia en la visita de screening.
g. Cualquier comorbilidad o tratamiento con fármacos experimentales que a criterio del investigador pudieran alterar los resultados del estudio o conllevar riesgos adicionales para el participante.
h. Participantes que reciban medicación contraindicada según la ficha técnica de la medicación del estudio.
i. Insuficiencia hepática severa (Clase C) determinada por la clasificación Child-Pugh.
j. Alanina aminotransferasa (ALT) por encima de 5 veces el límite superior de la normalidad (LSN) o ALT por encima de 3xLSN y bilirrubina por encima de 1.5xLSN.
k. Enfermedad hepática inestable (definida por la presencia de ascitis, encefalopatía, coagulopatía, hipoalbuminemia, varices gástricas o esofágicas o ictericia persistente), cirrosis, anormalidades biliares conocidas (con la excepción de hiperbilirrubinemia o ictericia debido a síndrome de Gilbert o colelitiasis asintomática).
l. Aclaramiento de creatinina<30 mL/min/1.73m2 por CKD-EPI.
m. Cualquier anormalidad de laboratorio Grado 4 confirmada que, a criterio de los investigadores, pudiera afectar a la seguridad del participante si se incluyera en el estudio.
n. Historia o presencia de alergia a dolutegravir o lamivudina. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of virologic failure (VF) defined as HIV-1 RNA viral load (VL) ≥ 50 copies per mL at 48 weeks (in the intention-to-treatexposed population (ITT-e) using the US Food and Drug Administration (FDA) snapshot algorithm). |
| Proporción de fracasos virológicos (FV), definido como carga viral (CV) VIH-ARN ≥ 50 copias/mL a 48 semanas (población intención de tratar-expuesta (ITT-e), algoritmo snapshot de la Food and Drug Administration [FDA]). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
- Proportion of VF (≥50 copies/mL) at week 96, ITT-e, FDA snapshot.
- Proportion of VF (≥50 copies/mL) atweek 48 and 96, per protocol population (PP), FDA snapshot.
- Proportion of VF (≥200 copies/mL) at week 48 and 96, ITT-e and PP population, FDA snapshot.
- Proportion of Confirmed Virologic Withdrawal ([CVW]: A VL≥ 50 copies/mL followed by a VL≥ 200 copies/mL in retest) at weeks 48 and 96, ITT-e and PP population, FDA snapshot.
- Proportion of Precautionary Virologic Withdrawal ([PVW]: three consecutive VL between 50- 200 copies/mL) at weeks 48 and 96, ITT-e and PP population, FDA snapshot.
- Proportion of participants with VL<50 copies/mL week 48 and 96, ITT-e and per protocol population, FDA snapshot.
- Incidence of VF with drug resistance aations.ssociated mut
- Describe number and type of resistanceassociated mutations in VF
- Analysis of factors associated to VF (i.e time to VF).
- Proportion of VF in pre-specified subgroups:
- Confirmed historical M184V/I vs No resistance mutations
- INSTI exposure vs No prior INSTI exposure
- Time virologically suppressed
- Time on 3TC/FTC
- Proportion of participants with VF with baseline 3TC or INSTI resistanceassociated mutations detected at baseline by NGS with 1, 5, and 20% threshold.
- Proportion of participants with transient viral rebounds with baseline 3TC or INSTI resistance- associated mutations detected at baseline by NGS with 1, 5, and 20% threshold.
- Type and frequency of resistance mutations (RT and integrase) in proviral DNA measured by NGS at baseline and week 96.
- Change from Baseline in CD4+ cell count and in CD4+/CD8+ cell counts ratio at weeks 48 and 96
-Incidence and severity of AEs and laboratory abnormalities through week 48 and 96.
- Proportion of subjects who discontinue treatment due to AEs through weeks 48 and 96. |
- Proporción de FV (≥50 copias/mL) a semana 96, ITT-e, FDA snapshot.
- Proporción de FV (≥50 copias/mL) a semanas 48 y 96, población por protocolo (PP), FDA snapshot.
- Proporción de FV (≥200 copias/mL) a semanas 48 y 96, población ITT-e y PP, FDA snapshot.
- Proporción de Retiradas Virológicas Confirmadas ([RVC]: Una CV≥ 50 copias/mL seguida de una CV≥ 200 copias/mL en el re-test) a semanas 48 y 96, población ITT-e y PP, FDA snapshot.
- Proporción de Retiradas Virológicas Preventivas ([RVP]: tres CV consecutivas entre 50- 200 copias/mL) a semanas 48 y 96, población ITT-e y PP, FDA snapshot.
- Proporción de participantes con CV VL<50 copias/mL a semanas 48 y 96, población ITT-e y PP, FDA snapshot.
- Incidencia de FV con mutaciones de resistencia a fármacos.
- Describir el número y tipo de mutaciones de resistencia en el FV.
- Análisis de factores asociados al FV (ej.
tiempo hasta el FV).
- Proporción de FV en subgrupos preespecificados:
- M184V/I histórica confirmada vs. No mutaciones de resistencia.
- Exposición previa a INI vs. No exposición previa a INI.
- Tiempo de supresión virológica.
- Tiempo con 3TC/FTC.
- Proporción de participantes con FV con mutaciones de resistencia a 3TC o INI detectadas basalmente mediante NGS con los límites del 1,5 y 20%.
- Proporción de participantes con repuntes virales transitorios con mutaciones de resistencia a 3TC o INI detectadas basalmente mediante NGS con los límites del 1,5 y 20%.
- Tipo y frecuencia de mutaciones de resistencia (RT e integrasa) detectadas mediante NGS de ADN proviral en visita basal y a semana 96.
- Cambio desde la visita basal en cifras de CD4+ y ratio CD4+/CD8+ a semanas 48 y 96.
- Incidencia y severidad de EAs y alteraciones de laboratorio a semanas 48 y 96.
- Proporción de sujetos que discontinúan el tratamiento debido a EAs a semanas 48 y 96. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Weeks 48 and 96 |
| Semana 48 y 96 |
|
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 17 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 | No |
| 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
|
| LPLV |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
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