SNPMiner Trials by Shray Alag


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Report for Mutation E138G

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

There are 4 clinical trials

Clinical Trials


1 Prospective Clinical Trial to Assess Safety and Efficacy of DRV/r(TMC 114/r), ETV(TMC 125) and MK-0518 in Addition to OBT in HIV-1 Infected Patients With Limited to No Treatment Options ANRS 139 TRIO

The purpose of this study is to look at the safety and efficacy of a combination of 3 new antiretroviral drugs: darunavir, etravirine and MK-0518 (raltegravir) in patients who have multi-resistant viruses and limited treatment options. An optimized background regimen that may include nucleoside reverse transcriptase inhibitors (NRTIs) and enfuvirtide can be added, if possible, to this combination. Patients will undergo treatment for 48 weeks and virological efficacy will be evaluated at week 24.

NCT00460382 HIV Infections Drug: raltegravir potassium Drug: darunavir/ritonavir Drug: etravirine Drug: Optimized background regimen
MeSH: HIV Infections

- Genotypic resistance testing at the screening visit: - Protease inhibitor mutations: over or equal to 3 primary protease inhibitor mutations among: D30N, V32I, L33F, M46I/L, I47A/V, G48V, I50L/V, I54M, L76V, V82A/F/L/T/S, I84V, N88S and L90M (IAS list 2006) but below or equal to 3 mutations among the following: V11I, V32I, L33F, I47V, I50V, I54L/M, G73S, L76V, I84V et L89V (virus sensitivity to darunavir/ritonavir). - Reverse transcriptase mutations: over or equal to 3 NRTI mutations (among IAS list) and below or equal to 3 mutations among: A98G, L100I, K101Q/P/E, K103H/N/S/T, V106A/M, V108I, E138G/K/Q, V179D/E/F/G/I, Y181C/I/V/C/H/L, Y188C/H/L, G190A/C/E/Q/S, P225H, F227C/L, M230I/L, P236L, K238N/T and Y318F (virus sensitivity to etravirine) Exclusion Criteria: - Non effective barrier contraception in women of child bearing potential - Pregnant women or women who are breastfeeding - Opportunistic infection at the acute phase - Decompensated cirrhosis (stage B or C of Child-Pugh score) - Malignancy requiring chemotherapy or radiotherapy - Contraindicated medications being taken by the patient (listed in protocol) - Allergy to the active substances and expedients of darunavir, etravirine and raltegravir. --- D30N --- --- V32I --- --- L33F --- --- M46I --- --- I47A --- --- G48V --- --- I50L --- --- I54M --- --- L76V --- --- V82A --- --- I84V --- --- N88S --- --- L90M --- --- V11I --- --- V32I --- --- L33F --- --- I47V --- --- I50V --- --- I54L --- --- G73S --- --- L76V --- --- I84V --- --- L89V --- --- A98G --- --- L100I --- --- K101Q --- --- K103H --- --- V106A --- --- V108I --- --- E138G ---

Primary Outcomes

Measure: Proportion of patients with HIV RNA levels of less than 50 copies/ml in an intent to treat analysis at week 24

Time: week 24

Secondary Outcomes

Measure: Proportions of patients with HIV RNA levels of less than 50 copies/ml at week 48, with HIV RNA levels of less than 400 copies/ml at weeks 24 and 48

Time: week 24 and 48

Measure: HIV RNA level evolution between baseline and week 48

Time: from week 0 to 48

Measure: HIV proviral DNA and 2LTR circle HIV DNA between baseline and week 48

Time: from week 0 to 48

Measure: Number and type of resistance mutations in case of virologic failure occurrence

Time: from week 0 to 48

Measure: CD4 lymphocyte count and proportion evolution between baseline and week 48

Time: from week 0 to 48

Measure: HIV infection progression

Time: from week 0 to 48

Measure: Frequency of the study regimen modifications and interruption

Time: from week 0 to 48

Measure: Study regimen tolerance

Time: from week 0 to 48

Measure: Study regimen adherence

Time: from week 0 to 48

Measure: Association between study drugs' minimum concentrations at week 4 and week 12 and virologic success at week 24

Time: from week 4 to 24

Measure: Evolution of pharmacokinetics parameters of study drugs in the PK substudy

Time: betwwen week 1 and 4

2 A Phase IV, Open-label Single-arm Study Investigating the Pharmacokinetics and Pharmacodynamics of the Antiretroviral Combination of Rilpivirine and Ritonavirboosted Darunavir in Therapy-naive HIV-1 Infected Patients.

For patients who are starting to take antiretroviral medication (to treat HIV) for the first time, there are now a variety of different medicines which may be taken together as a combination in order to form an effective treatment which suppresses the virus for prolonged periods of time. Currently, national guidelines recommend the use of two different drugs of one type (the nucleoside/ nucleotide reverse transcriptase inhibitors, NRTI often known as "nukes") with a third drug from one of two other types (either a nonnucleoside reverse transcriptase inhibitor, known as an NNRTI or "nonnuke", or a protease inhibitor, known as a PI) to form a treatment regime of three active drugs. In the UK and Europe, all PIs are given in combination with a small dose of a second PI, ritonavir, which has the effect of boosting the levels of the active PI in the bloodstream. The investigators know from both research studies and patient experience in clinic that a combination of a ritonavirboosted PI with an NNRTI achieves similar results in suppressing the HIV virus, compared to the use of either a PI or NNRTI with 2 NRTI as described above. In this study, the investigators will observe the combination of two licensed antiretroviral medications, ritonavirboosted darunavir(DRV/r) and rilpivirine (RPV), in suppressing virus when given to patients who are commencing treatment for HIV infection for the first time. Both of these drugs are licensed for treatment of patients with HIV in the UK and Europe, and are currently in standard clinical use. The study will monitor this treatment over the first 48 weeks. The investigators will also examine the levels of both drugs in the bloodstream during the first 4 weeks of starting this regimen, to confirm that they remain at levels which the investigators know to be effective against the virus.

NCT01736761 HIV Drug: Darunavir, Ritonavir and Rilpivirine

- Disallowed concomitant medication as per the summary of product characteristics for darunavir or rilpivirine (see section 5.2). - Any genotypic resistance mutations on screening or prior tests to darunavir (V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V) or rilpivirine (K101E, K101P, E138A, E138G, E138K, E138R, E138Q, V179L, Y181C, Y181I, Y181V, H221Y, F227C, M230I, and M230L). --- V11I --- --- V32I --- --- L33F --- --- I47V --- --- I50V --- --- I54M --- --- I54L --- --- T74P --- --- L76V --- --- I84V --- --- L89V --- --- K101E --- --- K101P --- --- E138A --- --- E138G ---

Primary Outcomes

Description: To describe the rate of virologic suppression after 48 weeks of therapy with the study regime. This will be measured by the proportion of patients with HIV-1 RNA ≤ 40 copies/mL at week 48

Measure: Virologic suppression after 48 weeks of therapy with the study regime

Time: 48 weeks

Secondary Outcomes

Description: The proportion of enrolled patients with a reduction from baseline in HIV-1 RNA >1 log10 copies /mL at weeks 4, 8, 12 and proportion with HIV-1 RNA ≤400 copies/mL at week 24.

Measure: To explore the virologic response to this combination rilpivirine and ritonavir-boosted darunavir at weeks 4, 8, 12 and 24 of therapy.

Time: 24 weeks

Other Outcomes

Description: The PK parameters (Cmax, C24, AUC0-24, and t1/2) for darunavir, rilpivirine and ritonavir at steady-state on day 28

Measure: To investigate the plasma pharmacokinetics of darunavir, ritonavir and rilpivirine when given in combination

Time: Day 28

3 Effect of SwitChing AtriPla to Eviplera on Neurocognitive and Emotional Functioning, ESCAPE Study

This study will evaluate the effects of switching Atripla to Eviplera on neurocognition measured by neuropsychological testing and functional MRI

NCT02308332 Neurocognitive Decline HIV Associated Neurocognitive Disorder Drug: Eviplera
MeSH: Neurocognitive Disorders

Differences in mean changes between baseline and end of study, as well as between the two study groups will be calculated using a paired T-test.. Inclusion Criteria: - Male, between 30 and 50 years - HIV-1 RNA < 50 copies/mL on screening visit - on Atripla continuously for ≥6 months preceding the screening visit - Have a HIV genotype prior to starting cART with Atripla with no known resistance to any of the study agents at any time in the past including, but not limited to RT mutations K65R, K101E/P, E138G/K/Q/R, Y181C/I/V, M184V/I and H221Y - Negative TPHA or VDRL < 12 months prior to the screening visit - no signs of an acute or chronic hepatitis C infection within the past 12 months before screening as defined in the Dutch guideline (Arends et al. --- K65R --- --- K101E --- --- E138G ---

Inclusion Criteria: - Male, between 30 and 50 years - HIV-1 RNA < 50 copies/mL on screening visit - on Atripla continuously for ≥6 months preceding the screening visit - Have a HIV genotype prior to starting cART with Atripla with no known resistance to any of the study agents at any time in the past including, but not limited to RT mutations K65R, K101E/P, E138G/K/Q/R, Y181C/I/V, M184V/I and H221Y - Negative TPHA or VDRL < 12 months prior to the screening visit - no signs of an acute or chronic hepatitis C infection within the past 12 months before screening as defined in the Dutch guideline (Arends et al. --- K65R --- --- K101E --- --- E138G ---

Primary Outcomes

Description: Patients will undergo a neuropsychological test battery where multiple standardized test will be undertaken to assess 7 different domains; Verbal Fluency, Executive Functioning, Speed of Information Processing, Learning, Memory, Attention/Working Memory, Motor skills. Raw scores can be calculated per domain and as a composite score. Differences in mean changes in composite score between baseline and end of study will be assessed with a paired T-test. A p-value <0.05 will be considered statistically significant. Within-arm changes will be assessed using Wilcoxon signed rank tests, and between-group comparisons will be evaluated with Wilcoxon rank sum tests. Multivariate analyses will be performed to analyse differences in the primary endpoints between the study groups.

Measure: To evaluate the neurocognitive performance as measured by neuropsychological test composite score after 12 weeks in stable HIV-infected patients switched from Atripla to Eviplera compared to a control group of patients on Atripla.

Time: 12 weeks

Secondary Outcomes

Description: The aim is to investigate if there is a correlation between improvement on neuropsychological test scores after 12 weeks of Eviplera therapy, and changes on fMRI after 12 weeks of Eviplera therapy. If there is a correlation, that means fMRI could be used to evaluate neurocognitive decline. Basically, we will asses if there is a correlation between ∆neuropsychological score and ∆fMRI-score. Because this is ordinal data, we will use a Spearman rank-order correlation to calculate a correlation-coefficient.

Measure: to assess the correlation between neurocognitive improvement (neuropsychological evaluation) and functional imaging (fMRI) after switching Atripla to Eviplera

Time: 12 weeks

Description: The aim is if an improvement in neuropsychological test scores after 12 weeks of Eviplera therapy is correlated with an improvement of quality of life. Basically, we will assess if there is a correlation between ∆neuropsychological score and ∆SF-36 total score. Because this is ordinal data, we will use a Spearman rank-order correlation to calculate a correlation-coefficient.

Measure: to evaluate correlation between neurocognitive performance and health related quality of life measured by SF-36 total score after switching from Atripla to Eviplera.

Time: 12 weeks

Measure: to assess the emotional functioning measured by HADS total score after switching Atripla to Eviplera by using a paired T-test to calculate differences in mean changes between baseline and end of study

Time: 12 weeks

Measure: to assess USER-P (total scores) after switching Atripla to Eviplera

Time: 12 weeks

Description: With this study, we want to investigate the effect of switching Efavirenz (as a component of Atripla) to Rilpivirine (as a component of Eviplera) on neurocognition. Our hypothesis is that neurocognition (as measured by neuropsychological testing scores) will improve when switching from Efavirenz (as a component of Atripla). If that is the case, hypothetically a lower or higher drug level of Efavirenz (as a component of Atripla) could have an effect on neurocognition (as measured by neuropsychological test scores). We will assess the correlation between drug level of Efavirenz or Rilpivirine and changes in neurocognitive function as measured by neuropsychological testing, and fMRI changes by regression analyses using drug levels as an independent variable and neuropsychological test scores as a dependent variable.

Measure: to assess drug levels of Efavirenz (as a component of Atripla) and Rilpivirin (as a component of Eviplera) in relation to changes in neurocognitive performance and fMRI in both patient groups.

Time: 12 weeks

Description: In our study, we will use the PROMIS instruments Anxiety, Depression, Sleep disturbance and Satisfaction with social roles and activities. These are all short forms containing 8 questions or statements. Patients are asked to rate the questions from 1-5 into which extent they believe them to be true; 1 being not at all and 5 being very much. For each short form, a score will be calculated by adding the values of the response to each question. PROMIS provides a score conversion table where the score can be translated into a T-score. This rescales the patient's score into a standardized score with a mean of 50 and a standard deviation of 10. In order to provide these results, PROMIS uses a calibration sample containing data from over 21000 respondents. Differences in mean changes between baseline and end of study, as well as between the two study groups will be calculated using a paired T-test.

Measure: to evaluate the usefulness of PROMIS instruments in HIV research

Time: 12 weeks

4 A Phase IV 48 Week, Open Label, Pilot Study of Darunavir Boosted by Cobicistat in Combination With Rilpivirine to Treat HIV+ Naïve Subjects (PREZENT)

Current HIV treatment guidelines recommend the use of triple-drug therapy (two nucleoside reverse transcriptase inhibitors and either a protease inhibitor, non-nucleoside reverse transcriptase inhibitor, or an integrase inhibitor) for the treatment of antiretroviral (ARV)-naïve patients. With the introduction of highly active antiretroviral therapy (HAART), patients with HIV are living much longer. With the increasing lifespan of persons with HIV, long-term complications from therapy as well as the occurrence of co-morbidities with aging have prompted HCPs to re-think the current treatment paradigm and consider novel combinations of ARVs. All of the currently approved HIV antiretrovirals have been implicated in causing long-term toxicities; however the greatest body of evidence for long-term metabolic effects has implicated the nucleoside reverse transcriptase (NRTI) class. By utilizing a non-NRTI treatment regimen, it is hypothesized that many of these long-term metabolic effects (renal toxicity, bone loss, body fat changes) can be delayed or avoided altogether. The clinical data on novel combinations is currently limited but rapidly growing and has included several combinations that have utilized darunavir. This study will be the first of its kind using the unique combination of darunavir/cobicistat and rilpivirine. Currently, this drug combination is not a recommended option for first time treatment of HIV

NCT02404233 HIV Positive Drug: darunavir/cobicistat Drug: rilpivirine
MeSH: HIV Seropositivity

Exclusion Criteria 1. Patient with active AIDS-defining opportunistic infection or disease according to the 1993 CDC AIDS surveillance definition (Clinical Category C) in the 30 days prior to baseline and that, in the opinion of the investigator, would preclude the patient from participating in the study (See Appendix C). 2. Patient has none of the following darunavir-associated RAMs: V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, L89V 3. Having documented genotypic evidence of NNRTI resistance at screening or from historical data available in the source documents, i.e. at least one of the NNRTI rams from the following list; K101E, K101P, E138A, E138G, E138K, E138R, E138Q, , V179L, Y181C, Y181I, Y181V, Y188L, H221Y, F227C, M230I, M230L, or the combination of the K103N and L100I. --- V11I --- --- V32I --- --- L33F --- --- I47V --- --- I50V --- --- I54L --- --- I54M --- --- T74P --- --- L76V --- --- I84V --- --- L89V --- --- K101E --- --- K101P --- --- E138A --- --- E138G ---

Primary Outcomes

Measure: Proportion of patients with plasma HIV-1 RNA <50 copies/mL

Time: up to weeks 48

Secondary Outcomes

Measure: Proportion of patients with plasma HIV-1 RNA <400 copies/mL at each time point evaluated

Time: At week 4, week 12, week 24, week 36, week 48

Measure: Number of weeks until HIV RNA <400 copies/mL and <50 copies/mL, respectively

Time: At week 4, week 12, week 24


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