Ignite Creation Date:
2024-05-06 @ 5:35 PM
Last Modification Date:
2024-10-26 @ 2:32 PM
Study NCT ID:
NCT05362916
Status:
RECRUITING
Last Update Posted:
2023-10-19
First Post:
2022-04-22
Brief Title:
Letermovir in ART-treated HIV-infected Persons
Sponsor:
Jean-Pierre Routy
Organization:
McGill University Health CentreResearch Institute of the McGill University Health Centre
Study Overview
Official Title:
Influence of a 3-month Letermovir Treatment on Gut Inflammation in ART-treated HIV-infected Persons in an Open Labelled Controlled Randomized Study
Status:
RECRUITING
Status Verified Date:
2023-10
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
Letermovir
Brief Summary:
This is a multi-centre open-label randomized controlled clinical trial to assess the influence of letermovir on gut translocation marker LPS in blood in ART-treated cytomegalovirus CMV-seropositive adult people living with HIV PLWH The study will explore the influence of letermovir treatment on gut damage with no intention for label change Participants n60 should have a cluster of differentiation 4 cells CD4 count greater than 400 cellsµl and a negative viral load Forty 40 participants will be randomized to receive letermovir PREVYMIS 480 mg or 2x240mg orally in addition to their usual ART and 20 participants will receive standard of care alone ART only for 14 weeks Study visits will include screening 2 baselines followed by follow-up visits at 2 and 4 weeks and at 14 weeks after starting treatment and 12 weeks after end of letermovir treatment to assess a carry-over effect
In an optional sub-study colonoscopies and colon biopsies will be performed before and after letermovir treatment or standard of care alone to assess gut mucosa inflammation
In an optional sub-study colonoscopies and colon biopsies will be performed before and after letermovir treatment or standard of care alone to assess gut mucosa inflammation
Detailed Description:
INTRODUCTION BACKGROUND AND STUDY RATIONALE
Cytomegalovirus CMV seropositivity is frequent in the general population and even more so in persons living with HIV PLWH In the general population high anti-CMV immunoglobulins G IgG-titer has been associated with earlier mortality cluster of differentiation 8 CD8 T-cell expansion low CD4CD8 ratio and increased cluster of differentiation cells CD57 senescence marker expression on T cells Such elevated IgG titer may be linked to transient CMV replication The investigators have shown that gut permeability is correlated with anti-CMV IgG titers in PLWH on antiretroviral therapy ART Increased gut permeability is associated with microbial translocation and systemic inflammation and correlates with frequency of non-infectiousnon-AIDS comorbidities such as cardiovascular diseases neurocognitive disorders and cancer Moreover gut permeability has been linked with reduced response to commercialized vaccines The investigators recently demonstrated that in HIV elite controllers a rare subgroup of PLWH who can control HIV replication in absence of ART CMV coinfection and anti-CMV IgG levels were associated with CD4 count decay As HIV replication is well controlled with ART our findings suggest that CMV co-infection is a driving factor behind increased gut permeability and inflammation in PLWH contributing to immune exhaustion and senescence
Hunt et al have shown that administration of valganciclovir an anti-CMV medication in ART-treated PLWH for 4 weeks was associated with a decrease in immune activation markers compared to the control group However long-term use of valganciclovir is not convenient due to its toxicity and its activity is not specific to CMV Furthermore its influence on gut permeability has not been assessed
A novel anti-CMV agent with an excellent safety profile letermovir was approved in 2017 for anti-CMV prophylaxis in allogeneic hematopoietic cell transplant recipients In these patients a drastic reduction of both low-grade replication and CMV infections combined with an improved immune reconstitution after the graft was reported In vitro in intestinal tissues reconstituted from primary cells letermovir anti-CMV treatment could prevent CMV-induced epithelial disruption
Potential Risks and Benefits to Human Participants
Potential Risks Associated with letermovir
For this study participants will be receiving two tablets of 240mg or one tablet of 480mg of PREVYMIS daily for 14 weeks in total This corresponds to the dose recommended for anti-CMV prophylaxis in hematopoietic cell transplant recipients In this latter population which is the only one for which PREVYMIS has been approved in Canada most frequent side effects are nauseavomiting and peripheral edema Cardiac events constitute 13 of all adverse effects including atrial fibrillation in 35 as such an ECG will be performed during the screening visit and participants with any type of known arrythmia will be excluded In case of cardiac symptoms during follow-up another ECG will be performed and participants with arrythmia will be withdrawn from the study and referred to a cardiologist In practice those side effects are unfrequent as illustrated in the pivotal clinical trial of letermovir in which frequency and severity of adverse events were not statistically increased in the letermovir group compared to placebo group
Finally based on the Canadian PREVYMIS monograph drug-on-drug interactions are possible and the concomitant administration of following medications will constitute exclusion criteria pimozide ergotamine lovastatin rosuvastatin simvastatin or bosentan when co-administered with cyclosporine For patients not using cyclosporine dose of statins will be reduced by 50 for the duration of the letermovir or placebo treatment Due to the long-term effect of statins such a short-period of dose reduction is not expected to increase cardiovascular risk to participants Regarding HIV medication exclusionary agents include darunavir efavirenz etravirine and nevirapine Those drugs constitute parts of ART regimens and participants who receive them will need to be excluded However this should not significantly impact recruitment as these drugs are only rarely prescribed in HIV clinics in Quebec
Exclusionary agents have been discussed and accepted by the Merck Investigator Studies Program Safety Committee of Merck
Potential risks to blood draws
The risks of drawing blood from a vein include discomfort at the blood draw site often momentary possible bruising redness swelling andor bleeding at the site will be managed by putting pressure on site of draw feeling of lightheadedness when blood is drawn will be managed by ensuring participants remains seated until dizziness abates and rarely an infection at the site where the blood was drawn cleaning of the site prior to blood draw should prevent this from happening and treatment in case of infection will be provided
Potential risks andor discomforts to colon mucosal biopsies
Participants from McGill University Health Centre MUHC will be invited to participate in an optional sub-study to collect colon mucosal biopsy They will be asked to sign a separate consent form if they wish to take part in the sub-study
The day before this procedure the consenting participant will be required to take measures to clear hisher bowels for the examination by drinking a picosulfate based solution and magnesium citrate as enunciated in the colonoscopy information preparation sheet Appendix 5
The Information sheet addendum will be given to each participant referring side effects risks contraindications and the medication interactions for the two magnesium-based products used to clean their bowels
During the colon mucosal biopsy procedure the participant may feel pressure in the rectum similar to the sensation felt with the urge to have a bowel movement The participant may also feel a small amount of abdominal cramping The most serious risk of the procedure is perforation ie poking a hole in the lining of the intestine this risk is extremely uncommon occurring once out of every 10000 procedures Some bleeding will likely occur at the place where the biopsies are done Light to moderate sedation using midazolam and fentanyl could be used during the procedure in the absence of any contraindication This sedation procedure is very safe rare side effects include temporary memory loss blood pressure drop or vomiting If the participant experiences severe discomfort despite sedation during the colon mucosal biopsies the procedure will be stopped immediately heshe will be seen by a physician and the research nurse will monitor himher until heshe is ready to go home
134 Benefits to Participating in This Study
The effects of CMV latent infection has been widely reported and include persisting inflammation gut leakage decreased response to vaccines and to pathogens As such a potential beneficial effect of letermovir on those parameters is expected which is particularly meaningful in the light of the current COVID-19 pandemic Altogether findings from this study may clarify the influence of CMV on health and help to improve treatments for PLWH The studys results will be published and all participants will be given access to the study findings
Study Rationale
Latent CMV infection and occasional replication has been linked with poorer outcome in PLWH Our hypothesis is that inhibiting CMV replication with a safe anti-CMV agent as letermovir will prevent gut damage and favor gut epithelium repair decreasing microbial translocation and lower non-AIDS comorbidity risks in ART-treated PLWH
Based on our experience and recent trials such at the single arm Clinical Trials Network CTN PT27 Lilac study the investigators propose a randomized controlled trial with a control arm receiving standard of care ART only to ensure the specificity of any changes the investigators could observe with letermovir long term ART treatment could influence inflammation markers Such a design is optimal for the development of future larger studies in the case where results would show a clinical interest
STUDY OBJECTIVES AND DESIGN
Overall Study Design
This is a multi-centre open-label randomized controlled clinical trial to assess the influence of letermovir on gut translocation marker LPS in blood in ART-treated CMV-seropositive adult PLWH The study will explore the influence of letermovir treatment on gut damage with no intention for label change Participants n60 should have a CD4 count greater than 400 cellsµl and a negative viral load Forty 40 participants will be randomized to receive letermovir PREVYMIS 480 mg or 2x240mg orally in addition to their usual ART and 20 participants will receive standard of care alone ART only for 14 weeks Study visits will include screening 2 baselines followed by follow-up visits at 2 and 4 weeks and at 14 weeks after starting treatment and 12 weeks after end of letermovir treatment to assess a carry-over effect
In an optional sub-study colonoscopies and colon biopsies will be performed before and after letermovir treatment or standard of care alone to assess gut mucosa inflammation
Primary Objectives
To assess the influence of CMV replication inhibition with letermovir on gut translocation markers LPS in blood of PLWH
Secondary Objectives
To assess the influence of CMV replication inhibition with letermovir on
Gut permeability markers in blood of PLWH REG3α and I-FABP Inflammation markers IL-6 sCD14 hsCRP d-dimers in blood of PLWH Anti-CMV immune response anti-CMV IgG titers and specific T-cell response and CMV DNA detection in plasma and Peripheral Blood Mononuclear Cells PBMC
In a sub-study inflammation in colon biopsies obtained by coloscopy and in CMV DNA detection in gut mucosa
Exploratory Objectivess
To assess the influence of CMV replication inhibition with letermovir on
HIV reservoir size in blood and mucosal samples Microbiota composition
Sub-studies
In an optional sub-study colonoscopies and colon biopsies will be performed before and after letermovir treatment or standard of care alone to assess gut mucosa inflammation
Cytomegalovirus CMV seropositivity is frequent in the general population and even more so in persons living with HIV PLWH In the general population high anti-CMV immunoglobulins G IgG-titer has been associated with earlier mortality cluster of differentiation 8 CD8 T-cell expansion low CD4CD8 ratio and increased cluster of differentiation cells CD57 senescence marker expression on T cells Such elevated IgG titer may be linked to transient CMV replication The investigators have shown that gut permeability is correlated with anti-CMV IgG titers in PLWH on antiretroviral therapy ART Increased gut permeability is associated with microbial translocation and systemic inflammation and correlates with frequency of non-infectiousnon-AIDS comorbidities such as cardiovascular diseases neurocognitive disorders and cancer Moreover gut permeability has been linked with reduced response to commercialized vaccines The investigators recently demonstrated that in HIV elite controllers a rare subgroup of PLWH who can control HIV replication in absence of ART CMV coinfection and anti-CMV IgG levels were associated with CD4 count decay As HIV replication is well controlled with ART our findings suggest that CMV co-infection is a driving factor behind increased gut permeability and inflammation in PLWH contributing to immune exhaustion and senescence
Hunt et al have shown that administration of valganciclovir an anti-CMV medication in ART-treated PLWH for 4 weeks was associated with a decrease in immune activation markers compared to the control group However long-term use of valganciclovir is not convenient due to its toxicity and its activity is not specific to CMV Furthermore its influence on gut permeability has not been assessed
A novel anti-CMV agent with an excellent safety profile letermovir was approved in 2017 for anti-CMV prophylaxis in allogeneic hematopoietic cell transplant recipients In these patients a drastic reduction of both low-grade replication and CMV infections combined with an improved immune reconstitution after the graft was reported In vitro in intestinal tissues reconstituted from primary cells letermovir anti-CMV treatment could prevent CMV-induced epithelial disruption
Potential Risks and Benefits to Human Participants
Potential Risks Associated with letermovir
For this study participants will be receiving two tablets of 240mg or one tablet of 480mg of PREVYMIS daily for 14 weeks in total This corresponds to the dose recommended for anti-CMV prophylaxis in hematopoietic cell transplant recipients In this latter population which is the only one for which PREVYMIS has been approved in Canada most frequent side effects are nauseavomiting and peripheral edema Cardiac events constitute 13 of all adverse effects including atrial fibrillation in 35 as such an ECG will be performed during the screening visit and participants with any type of known arrythmia will be excluded In case of cardiac symptoms during follow-up another ECG will be performed and participants with arrythmia will be withdrawn from the study and referred to a cardiologist In practice those side effects are unfrequent as illustrated in the pivotal clinical trial of letermovir in which frequency and severity of adverse events were not statistically increased in the letermovir group compared to placebo group
Finally based on the Canadian PREVYMIS monograph drug-on-drug interactions are possible and the concomitant administration of following medications will constitute exclusion criteria pimozide ergotamine lovastatin rosuvastatin simvastatin or bosentan when co-administered with cyclosporine For patients not using cyclosporine dose of statins will be reduced by 50 for the duration of the letermovir or placebo treatment Due to the long-term effect of statins such a short-period of dose reduction is not expected to increase cardiovascular risk to participants Regarding HIV medication exclusionary agents include darunavir efavirenz etravirine and nevirapine Those drugs constitute parts of ART regimens and participants who receive them will need to be excluded However this should not significantly impact recruitment as these drugs are only rarely prescribed in HIV clinics in Quebec
Exclusionary agents have been discussed and accepted by the Merck Investigator Studies Program Safety Committee of Merck
Potential risks to blood draws
The risks of drawing blood from a vein include discomfort at the blood draw site often momentary possible bruising redness swelling andor bleeding at the site will be managed by putting pressure on site of draw feeling of lightheadedness when blood is drawn will be managed by ensuring participants remains seated until dizziness abates and rarely an infection at the site where the blood was drawn cleaning of the site prior to blood draw should prevent this from happening and treatment in case of infection will be provided
Potential risks andor discomforts to colon mucosal biopsies
Participants from McGill University Health Centre MUHC will be invited to participate in an optional sub-study to collect colon mucosal biopsy They will be asked to sign a separate consent form if they wish to take part in the sub-study
The day before this procedure the consenting participant will be required to take measures to clear hisher bowels for the examination by drinking a picosulfate based solution and magnesium citrate as enunciated in the colonoscopy information preparation sheet Appendix 5
The Information sheet addendum will be given to each participant referring side effects risks contraindications and the medication interactions for the two magnesium-based products used to clean their bowels
During the colon mucosal biopsy procedure the participant may feel pressure in the rectum similar to the sensation felt with the urge to have a bowel movement The participant may also feel a small amount of abdominal cramping The most serious risk of the procedure is perforation ie poking a hole in the lining of the intestine this risk is extremely uncommon occurring once out of every 10000 procedures Some bleeding will likely occur at the place where the biopsies are done Light to moderate sedation using midazolam and fentanyl could be used during the procedure in the absence of any contraindication This sedation procedure is very safe rare side effects include temporary memory loss blood pressure drop or vomiting If the participant experiences severe discomfort despite sedation during the colon mucosal biopsies the procedure will be stopped immediately heshe will be seen by a physician and the research nurse will monitor himher until heshe is ready to go home
134 Benefits to Participating in This Study
The effects of CMV latent infection has been widely reported and include persisting inflammation gut leakage decreased response to vaccines and to pathogens As such a potential beneficial effect of letermovir on those parameters is expected which is particularly meaningful in the light of the current COVID-19 pandemic Altogether findings from this study may clarify the influence of CMV on health and help to improve treatments for PLWH The studys results will be published and all participants will be given access to the study findings
Study Rationale
Latent CMV infection and occasional replication has been linked with poorer outcome in PLWH Our hypothesis is that inhibiting CMV replication with a safe anti-CMV agent as letermovir will prevent gut damage and favor gut epithelium repair decreasing microbial translocation and lower non-AIDS comorbidity risks in ART-treated PLWH
Based on our experience and recent trials such at the single arm Clinical Trials Network CTN PT27 Lilac study the investigators propose a randomized controlled trial with a control arm receiving standard of care ART only to ensure the specificity of any changes the investigators could observe with letermovir long term ART treatment could influence inflammation markers Such a design is optimal for the development of future larger studies in the case where results would show a clinical interest
STUDY OBJECTIVES AND DESIGN
Overall Study Design
This is a multi-centre open-label randomized controlled clinical trial to assess the influence of letermovir on gut translocation marker LPS in blood in ART-treated CMV-seropositive adult PLWH The study will explore the influence of letermovir treatment on gut damage with no intention for label change Participants n60 should have a CD4 count greater than 400 cellsµl and a negative viral load Forty 40 participants will be randomized to receive letermovir PREVYMIS 480 mg or 2x240mg orally in addition to their usual ART and 20 participants will receive standard of care alone ART only for 14 weeks Study visits will include screening 2 baselines followed by follow-up visits at 2 and 4 weeks and at 14 weeks after starting treatment and 12 weeks after end of letermovir treatment to assess a carry-over effect
In an optional sub-study colonoscopies and colon biopsies will be performed before and after letermovir treatment or standard of care alone to assess gut mucosa inflammation
Primary Objectives
To assess the influence of CMV replication inhibition with letermovir on gut translocation markers LPS in blood of PLWH
Secondary Objectives
To assess the influence of CMV replication inhibition with letermovir on
Gut permeability markers in blood of PLWH REG3α and I-FABP Inflammation markers IL-6 sCD14 hsCRP d-dimers in blood of PLWH Anti-CMV immune response anti-CMV IgG titers and specific T-cell response and CMV DNA detection in plasma and Peripheral Blood Mononuclear Cells PBMC
In a sub-study inflammation in colon biopsies obtained by coloscopy and in CMV DNA detection in gut mucosa
Exploratory Objectivess
To assess the influence of CMV replication inhibition with letermovir on
HIV reservoir size in blood and mucosal samples Microbiota composition
Sub-studies
In an optional sub-study colonoscopies and colon biopsies will be performed before and after letermovir treatment or standard of care alone to assess gut mucosa inflammation
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None