Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Class |
|---|---|
| ViiV Healthcare | INDUSTRY |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
This is a phase IV, open label, multicentre trial that will be taking place at 4 sites in the United Kingdom (UK). Efavirenz which is taken in combination with Kivexa® or as part of the combination pill, Atripla® is a recommended firstline regimen for the treatment of Human Immunodeficiency Virus-1 (HIV- 1) infection. Treatment against the HIV virus is also referred to as antiretroviral therapy.
Toxicity is the most common reason for modification of firstline therapy. Central Nervous System (CNS) side effects such as difficulty with sleeping & bad dreams are common side effect of Efavirenz based therapy and is one of the most frequent reasons for switching or discontinuing highly active antiretroviral therapy.
Dolutegravir is within a novel class of antiretroviral agents licensed in the UK for the treatment of HIV. In combination with Truvada®, it showed fewer side effects when compared to Efavirenz in other clinical studies, where patients were starting HIV treatment for the first time, or switching from other agents.
The purpose of the study is to investigate the benefits of switching away from Eefavirenz (in combination with Kivexa® or as part of the combination pill, Atripla®) to Dolutegravir in patients with CNS side effects (such as difficulty with sleeping, bad dreams etc).
The main aim of this study is to investigate the benefits of switching from Efavirenz (taken in combination with Kivexa®or as part of the combination pill, Atripla®) in patients with Central Nervous System (CNS) side effects (such as difficulty with sleeping, bad dreams etc). The study aims to investigate the effect of switching Efavirenz to Dolutegravir while continuing Truvada (tenofovir plus emtricitabine, two constituents of Atripla) or Kivexa. Dolutegravir will be the only new component of the combination.
In addition to the aims stated above, the study also aims:
To investigate whether switching to dolutegravir based combination Antiretroviral Therapy (cART) is associated with resolution of CNS toxicity (determined by CNS questionnaire) at 12 weeks post switch To investigate continued virological suppression at levels of <400 and <50 copies/ml in individuals switching to dolutegravircontaining cART at 4 and 12 weeks post switch To investigate changes in cluster of differentiation 4+ (CD4+) cell count in individuals switching to dolutegravircontaining cART over 12 weeks post switch To investigate the safety (laboratory and non CNS adverse events) of switching to dolutegravir based cART over 12 weeks post switch To investigate changes in quality of life in individuals switching to dolutegravir based cART as assessed by Quality of life (EuroQOL) questionnaires over 12 weeks post switch To investigate the impact of switching to dolutegravir based CART on anxiety and depression (as determined by Hospital Anxiety and Depression Score (HADS) over 12 weeks post switch To investigate changes in quality of sleep in individuals switching to dolutegravir based cART as per standardized sleep questionnaire at 4 and 12 weeks post switch To assess the impact of switching to dolutegravir based cART on adherence by standard questionnaire over 12 weeks post switch To investigate changes in neuropsychiatric function in individuals switching to dolutegravir based cART by CogState battery and Instrumental Activities of Daily Life (IADL) questionnaire over 12 weeks post switch To investigate changes in fasting cholesterol and triglycerides in individuals switching to dolutegravir based cART over 12 weekspost switch To investigate Efavirenz (EFV) plasma decay and its impact on Dolutegravir (DTG) concentrations following the switch (Maximum Concentration (Cmax), Minimum Concentration (Cmin), Area Under the concentration-time Curve (AUC) at weeks 1, 2 and 3 post switch) To investigate the association between genetic polymorphisms in drug disposition genes and drug exposure To assess changes in the levels of tryptophan, kynurenine, kynurenine/tryptophan ratio, neopterin, tumour necrosis factorα and interferonγ in plasma following treatment switch from efavirenz to dolutegravir.
To investigate the relationship between the immune activation biomarkers and the kynurenine/tryptophan ratio at baseline and post switch.
To investigate the relationship between the kynurenine/tryptophan ratio and measures of CNS toxicity and neurocognitive impairment at baseline and postswitch.
Not provided
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Arm 1 | Experimental | Truvada (tenofovir 245mg/emtricitabine 200mg) or Kivexa (abacavir 600mg/lamivudine 300mg) one tablet once daily plus Dolutegravir 50mg (one tablet) once daily |
|
| Arm 2 | Experimental | Atripla (efavirenz 600mg, emtricitabine 200mg, tenofovir 245mg) one tablet once daily, or Truvada (tenofovir 245mg/emtricitabine 200mg) or Kivexa (abacavir 600mg/lamivudine 300mg) one tablet once daily plus efavirenz 600mg one tablet once daily for 4 weeks. At week 4, efavirenz is switched to Dolutegravir 50mg (one tablet) once daily |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Dolutegravir, efavirenz, efavirenz/emtricitabine/tenofovir | Drug | Arm 1: Switch efavirenz to dolutegravir immediately (at baseline) for 12 weeks Arm 2: Continue on pre-study regimen (unchanged) for 4 weeks and then switch efavirenz to dolutegravir for 12 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Rate of neuropsychiatric and central nervous system (CNS) toxicity | The rate of neuropsychiatric and central nervous system (CNS) toxicity (as measured by a questionnaire based on EFV Summary of Product Characteristics (SPC) and graded based on the ACTG adverse event scale) after 4 weeks of dual N(t)RTI plus DTG therapy:
| 4 weeks post switch, day1 |
| Measure | Description | Time Frame |
|---|---|---|
| Rate of neuropsychiatric and central nervous system (CNS) toxicity | The rate of neuropsychiatric and central nervous system (CNS) toxicity (as measured by a questionnaire based on EFV SPC and graded based on the ACTG adverse event scale) after 12 weeks of dual Nucleoside/Nucleotide Reverse Transcriptase Inhibitor (N(t)RTI) plus DTG therapy:
|
Not provided
Inclusion Criteria:
Exclusion Criteria:
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Nuno Morgado | Contact | +44 (0)20 3315 3765 | nuno.morgado@chelwest.nhs.uk |
| Name | Affiliation | Role |
|---|---|---|
| Mark Nelson, MD | St Stephen's AIDS Trust | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Chelsea and Westminster Hospital | London | SW10 9TH | United Kingdom |
Not provided
| ID | Term |
|---|---|
| C562325 | dolutegravir |
| C098320 | efavirenz |
| D000069480 | Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination |
| D000068257 | Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination |
| ID | Term |
|---|---|
| D000068698 | Tenofovir |
| D063065 | Organophosphonates |
| D009943 | Organophosphorus Compounds |
| D009930 | Organic Chemicals |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
|
| 12 weeks post switch, day1 |
| Virologic suppression | • Proportion of subjects maintaining virologic suppression to <50 and <400 copies/ml, 4 and 12 weeks post switch to dual N(t)RTI plus DTG | 4 and 12 weeks post switch, day1 |
| CD4 cell count and % | Change in CD4 cell count and % from baseline compared with 4 and 12 weeks post switch to dual N(t)RTI plus DTG | 4 and 12 weeks post switch, day1 |
| Quality of life | Changes in quality of life as assessed by Quality of life EuroQOL questionnaires at baseline, 4 and 12 weeks post switch | 4 and 12 weeks post switch, day1 |
| CNS toxicity | Change from baseline of CNS toxicity as measured by Hospital Anxiety and Depression (HADS) score at 4 and 12 weeks post switch to dual N(t)RTI plus DTG therapy, each compared with baseline | 4 and 12 weeks post switch, day1 |
| Sleep | Change in sleep from baseline compared with weeks 4 and 12 post switch to dual N(t)RTI plus DTG therapy, as determined by the Pittsburgh Sleep Score | 4 and 12 weeks post switch, day1 |
| Adherence | Change from baseline in adherence after 4 and 12 weeks of dual N(t)RTI plus DTG therapy as measured by the Medication Adherence Self-Report Inventory (M-MASRI) questionnaire | 4 and 12 weeks post switch, day1 |
| Neurocognitive assessment | Change from baseline in NeuroCognitive (NC) function after 4, and 12 weeks of dual N(t)RTI plus DTG therapy as determined by computerised NC assessment (CogState) and Instrumental Activities of Daily Life (IADL) questionnaire | 4 and 12 weeks post switch, day1 |
| Cholestrol levels | Change from baseline in median fasting cholesterol (total, HDL, LDL and total:HDL ratio) and triglycerides after switching to dual N(t)RTI plus DTG therapy at 4 and 12 weeks post switch | 4 and 12 weeks post switch, day1 |
| Laboratory values | Proportion of patients with grade 2-4 laboratory parameters (excluding lipids) after 4 and 12 weeks of dual N(t)RTI plus DTG therapy compared with baseline and proportion of patients with grade 2-4 non-CNS adverse events after 4 and 12 weeks of dual N(t)RTI plus DTG therapy compared with baseline | 4 and 12 weeks post switch, day1 |
| Efavirenz plasma concentration and Dolutegravir pharmacokinetics | Efavirenz plasma concentration decay and DTG Pharmacokinetics (PK) (Cmax, Cmin, AUC) at weeks 1, 2 and 3 post switch | 1, 2 and 3 weeks post switch, day1 |
| Protein levels | To assess changes in the levels of Triptophan (TRP), Kynurenic (KYN), KYN/TRP ratio, neomycin (NEO), Tumor Necrosis Factor (TNF-α) and Interferon (IFN-γ) in plasma at baseline/time of switch and 12 wks post-switch for all patients. | 12 weeks post switch, day1 |
| Difference in protein levels between the 2 arms | To assess differences between the immediate switch and delayed switch groups with regards to changes in the levels of TRP, KYN, KYN/TRP ratio, NEO, TNF-α and IFN-γ in plasma at baseline/time of switch and 12 wks post-switch | 12 weeks post switch, day1 |
| Relationship between immune activation markers and protein ratio | To investigate the relationship between the IA biomarkers and the KYN/TRP ratio at baseline and post-switch. | Baseline and post switch, day1 |
| Relationship between protein ratio and CNS toxicity and neurocognitive impairment | To investigate the relationship between the KYN/TRP ratio and measures of CNS toxicity and NCI at baseline and post-switch. | Baseline and post switch, day1 |
| D000068679 |
| Emtricitabine |
| D003841 | Deoxycytidine |
| D003562 | Cytidine |
| D011741 | Pyrimidine Nucleosides |
| D011743 | Pyrimidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D000225 | Adenine |
| D011687 | Purines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D003853 | Deoxyribonucleosides |
| D009705 | Nucleosides |
| D009706 | Nucleic Acids, Nucleotides, and Nucleosides |
| D004338 | Drug Combinations |
| D004364 | Pharmaceutical Preparations |
| D010078 | Oxazines |