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Advanced Neuroimaging Evaluation of CNS Changes Associated With Efavirenz Therapy Switch to an Raltegravir-based Regimen

18 juillet 2017 mis à jour par: Nina Lin, MD, Massachusetts General Hospital

Advanced Neuroimaging Evaluation of the Central Nervous System Biological Changes Associated With Efavirenz Therapy Switch to an Raltegravir-based Regimen

In this study investigators will use a multi-modal imaging approach of MRS and fMRI to comprehensively assess the biological changes in the brain associated with EFV-based regimen (EFV/FTC/TDF), specifically alterations in the brain circuitry, function and local neurochemistry, and their correlation with neuropsychological function.

Aperçu de l'étude

Statut

Complété

Les conditions

Intervention / Traitement

Description détaillée

In a cohort of HIV-infected patients who are clinically stable on the commonly use regimen of EFV/emtricitabine (FTC)/truvada (TDF) or Atripla, investigators propose to replace the EFV component with an integrase inhibitor, Raltegravir (RAL), given as the RAL and FTC/TDF to evaluate the EFV-related neural alterations. This is a multidisciplinary study which will be lead by Dr. Nina Lin, in collaboration with the research teams of Dr. Alexander Lin, Director of the Center for Clinical Spectroscopy, and Dr. Emily Stern, Director of the Functional Neuroimaging Laboratory, both members of the Brigham and Women's Department of Radiology at Harvard Medical School, as well as Dr. Jane Epstein, a researcher in Dr. Stern's research group. Dr. Epstein is a staff psychiatrist at Brigham and Women's hospital with extensive experience and expertise in research on abnormalities of affective and motivational processing in the context of neuropsychiatric disorders. Investigators will utilize the established clinical research platform in the Infectious Disease outpatient clinical practice at the Brigham and Women's Hospital, where there is currently have many ongoing HIV-related studies and a large panel of HIV-infected patients motivated to be involved in clinically relevant research. Investigators propose to use advanced neuroimaging to measure biologically changes in the brain associated with long-term EFV use with the following specific aims:

  1. Determine changes in neurometabolites measured by MRS in the brain associated with long-term EFV use
  2. Assess for alterations in neural activity correlated with affective symptoms associated with EFV vs RAL use using fMRI, and their associations with changes in neurometabolites assessed by MRS, and with changes in cognition assessed by Trail Making and Digit Substitution Tests.
  3. Determine changes in emotion, cognition and sleep quality after switching from EFV to RAL, and how they correlate with subject treatment preference.

This clinical study will extend our current understanding of EFV neurotoxicity by further defining the nature of these biological changes. Further elucidation of the neurobiological underpinnings of EFV-induced CNS toxicity will have clinical relevance in improving the quality of life and drug adherence of HIV-infected patients on ART, especially among older patients or those with baseline neuropsychiatric disorders, whom at baseline are more vulnerable to neurocognitive decline from long-term HIV infection.

Type d'étude

Interventionnel

Inscription (Réel)

10

Phase

  • N'est pas applicable

Contacts et emplacements

Cette section fournit les coordonnées de ceux qui mènent l'étude et des informations sur le lieu où cette étude est menée.

Lieux d'étude

  • États-Unis
    • Massachusetts
      • Boston, Massachusetts, États-Unis, 02115
        • Brigham and Women's Hospital

Critères de participation

Les chercheurs recherchent des personnes qui correspondent à une certaine description, appelée critères d'éligibilité. Certains exemples de ces critères sont l'état de santé général d'une personne ou des traitements antérieurs.

Critère d'éligibilité

Âges éligibles pour étudier

18 ans à 65 ans (Adulte, Adulte plus âgé)

Accepte les volontaires sains

Non

Sexes éligibles pour l'étude

Tout

La description

Inclusion Criteria:

  1. Chronic HIV-infected individuals on suppressive regimen with EFV/FTC/TDF, for at least 6 months
  2. Undetectable HIV-1 RNA virus load for at least 6 months
  3. No co-infections with active hepatitis B and C
  4. Presence of at least moderate symptoms on 2 out of 3 subcores on the DASS
  5. No known active HIV-related and non-HIV related CNS infections
  6. Estimated glomerular filtration rate (EGFR) >60 ml/min
  7. Consent to switching to EVG/COBI/FTC/TDF
  8. Ages 18 - 65

Exclusion Criteria:

  1. History of CNS opportunistic infections or active CNS infections
  2. History of severe psychiatric disorder (excluding depression and anxiety)
  3. History of chronic neurological disorders, such as epilepsy or multiple sclerosis
  4. History of or current significant substance abuse or dependence and/or heavy alcohol use (>12 oz/wk)
  5. Any women who may be pregnant (positive urine pregnancy test or unprotected sex in 2 weeks prior to scan) or known to be pregnant
  6. Contraindications to undergoing fMRI, including metallic implants, claustrophobia, and medical conditions or medications that significantly affect cerebral blood flow or function.

Plan d'étude

Cette section fournit des détails sur le plan d'étude, y compris la façon dont l'étude est conçue et ce que l'étude mesure.

Comment l'étude est-elle conçue ?

Détails de conception

  • Objectif principal: Science basique
  • Répartition: N / A
  • Modèle interventionnel: Affectation à un seul groupe
  • Masquage: Aucun (étiquette ouverte)

Armes et Interventions

Groupe de participants / Bras
Intervention / Traitement
Expérimental: Raltegravir
Switch from Atripla (EFV/FTC/TDF) to raltegravir (RAL) + Truvada (FTC/TDF). Raltegravir will be administered 400mg twice-a-day with Truvada for 8 weeks.
Médicament: Raltegravir
Switch from Atripla to Raltegravir 400mg BID + Truvada (FTC/TDF) for total of 8 weeks
Autres noms:
  • Raltegravir (Isentress) 400mg BID

Que mesure l'étude ?

Principaux critères de jugement

Mesure des résultats
Description de la mesure
Délai
Neurometabolites Based on Magnetic Resonance Spectroscopy (MRS)
Délai: week 0 and week 8
Assess the levels of neuro-metabolites measured by MRS at week 0 before switching to the efavirenz-based therapy. Two areas of the brain: 1) posterior cingulate gyrus and 2) anterior cingulate will be assessed for the levels of brain creatine (Cr), gamma-aminobutyric acid (GABA) and glutathione (GLU).
week 0 and week 8
Neural Activation Networks Using Functional Magnetic Resonance Imaging (fMRI)
Délai: week 0 and week 8
Assess changes in neural activation correlated with affective disturbances associated with EFV vs. RAL using fMRI employing a paradigm that probes affective symptomatologies typical with EFV use; anxiety/dysphoria and affective dysregulation, and their association with changes in cognitive function. Four brain regions of interests (ROIs) are specified to show the differential frontal-limbic activation patterns in the task-evoked neural responses to the 3 linear contrasts of Pre-/Post-/ Pre-vs. Post-switch: [Negative Word vs. Neutral Word] x [No-Go Trial Block vs. Go Trial Block]: anterior Frontal Pole (aFP), posterior Cingulate Gyrus (pCG), dorsal anterior Cingulate Gyrus (daCG), Left Hippocampus (LHC). A linear mixed-effects model is utilized to examine the effect sizes of the key Regimen/Condition contrasts, with the Subject factor as the random-effect, and Age incorporated as a co-variate of no interest. A z-score is the Mean with a SD=1 and Measure of Dispersion equal to 1.
week 0 and week 8

Mesures de résultats secondaires

Mesure des résultats
Description de la mesure
Délai
Other Neurometabolite Changes Measured by MRS
Délai: week 0 and week 8
Use MRS to evaluate a fuller panel of known neurometabolites (in addition to the primary endpoints) to evaluate for prominent and significant changes associated with EFV use.
week 0 and week 8
Neurocognitive Changes Measured by a Panel of Indexes: WAIS-R, HAMD, DASS-21, FRSBE, STAI
Délai: week 0 and week 8

Assess for changes in cognitive and affective function prior to and after switching off EFV-based regimen. Indexes used to access neurocognitive changes included:

  1. Wechsler Adult Intelligence Scale (WAIS-R) Digital Symbol Substitution Test: sensitive to brain dmamage, dementia, age and depressive changes. Range of 0-100, the higher the score the better the person's performance
  2. Hamilton Rating Scale for Depression (HAMD): Measure of depression. Score of 0-7 is normal, score of >20 is moderate/severe depression
  3. Depression Anxiety Stress Scale (DASS-21) the lower the score, the less severe depression, anxiety and stress. Scale range of 0-63
  4. Frontal Systems Behavior Scale (FRSBE): Increased score indicates greater behavioral impairment associated with frontal systems, range 37.2 to 186
  5. Spielberger state trait anxiety inventory (STAI): the higher the score the greater then anxiety level, range of 20 to 80.
week 0 and week 8
Fasting Lipid Profile
Délai: week 0 and week 8
Measure the change in fasting lipid panel prior to and after switching off EFV-based regimen.
week 0 and week 8
Sleep Quality
Délai: week 0 and week 8
Assess for changes in sleep pattern and quality prior to and after switching off EFV-based regimen through a self-administered Pittsburg Sleep Quality Index (PSQI). Measure consists of 19 items with each weighted on 0-3 scale and the sum produces a total score, which ranges from 0-21. The lower the score the healthier the sleep quality.
week 0 and week 8
ART Regimen Preference
Délai: week 0 and week 8
Evaluate patient preference in ART regimen (Atripla, EFV/FTC/TDF versus RAL + FTC/TDF) through self-administered questionnaires.
week 0 and week 8
Markers of Immune Activation
Délai: week 0 and week 8
Change in markers of immune activation and inflammation associated with change to RAL (ie, sCD14, IL-6, hsCRP, D-dimer, CRP, LPS, sCD163, EndoCab)
week 0 and week 8
Change in Level of EFV and Metabolites
Délai: week 0 and week 8
Correlate change in level of EFV and metabolites with neurocognitive and neuroimaging changes
week 0 and week 8

Collaborateurs et enquêteurs

C'est ici que vous trouverez les personnes et les organisations impliquées dans cette étude.

Parrainer

Massachusetts General Hospital

Collaborateurs

Merck Sharp & Dohme LLC

Les enquêteurs

  • Chercheur principal: Nina Lin, MD, Massachusetts General Hospital

Dates d'enregistrement des études

Ces dates suivent la progression des dossiers d'étude et des soumissions de résultats sommaires à ClinicalTrials.gov. Les dossiers d'étude et les résultats rapportés sont examinés par la Bibliothèque nationale de médecine (NLM) pour s'assurer qu'ils répondent à des normes de contrôle de qualité spécifiques avant d'être publiés sur le site Web public.

Dates principales de l'étude

Début de l'étude (Réel)

1 janvier 2014

Achèvement primaire (Réel)

1 septembre 2016

Achèvement de l'étude (Réel)

1 janvier 2017

Dates d'inscription aux études

Première soumission

20 octobre 2013

Première soumission répondant aux critères de contrôle qualité

31 octobre 2013

Première publication (Estimation)

7 novembre 2013

Mises à jour des dossiers d'étude

Dernière mise à jour publiée (Réel)

26 juillet 2017

Dernière mise à jour soumise répondant aux critères de contrôle qualité

18 juillet 2017

Dernière vérification

1 juillet 2017

Plus d'information

Termes liés à cette étude

Mots clés

Termes MeSH pertinents supplémentaires

Autres numéros d'identification d'étude

  • NeuroHIV002

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