Ignite Creation Date:
2025-12-18 @ 8:26 AM
Ignite Modification Date:
2025-12-23 @ 10:49 PM
Study NCT ID:
NCT02210715
Status:
None
Last Update Posted:
2023-10-19 00:00:00
First Post:
2014-08-05 00:00:00
Is Possible Gene Therapy:
False
Has Adverse Events:
False
Brief Title:
Raltegravir-based Antiretroviral Versus Maintaining Any Other Antiretroviral Therapy in HIV Mono-infected Patients
Sponsor:
None
Organization:
Study Overview
Official Title:
Randomized Study Comparing Switching to Raltegravir-based Antiretroviral Versus Maintaining Any Other Antiretroviral Therapy in HIV Monoinfected Patients Impact on Fatty Liver and Liver Fibrosis Assessed by Noninvasive Diagnostic Methods
Status:
None
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:
None
Brief Summary:
Current Non-invasive tools for liver fibrosis and fatty liver/NASH, including Fibroscan/CAP and serum cytokeratin 18 (CK-18), are accurate and ideal for screening and monitoring. To date, there has been no study using these accurate non-invasive tools to prospectively evaluate the effect of switching cART to raltegravir in HIV mono-infected patients with suppressed HIV RNA who have evidence of fatty liver and/or significant liver fibrosis in order to determine whether such a strategy may slow fibrosis and steatosis progression rates.
Once a candidate for screening has been identified, study details will be carefully discussed with the subject. The subject will be asked to read and sign the approved informed consent form prior to any assessments being performed. Self-administered questionnaires will collect information on Alcohol use and Disorders Identification Test (audit C), drug use. chart review, (demographics, medication medical history).
Blood samples will be obtained for clinical laboratory evaluations (as per standard of care) at baseline, and all follow-up visits, plus serum CK-18 that will be obtained at all follow-up visits. Routine hematology and chemistry evaluations will include: complete blood count (CBC) with differential, CD4 and CD8 cell counts, viral load, C-reactive Protein, D-dimer, and measurements of hepatic, pancreatic and renal function, fasting insulin, creatine kinase, glucose and lipid profiles. Plasma HIV RNA levels will be measured with a lower limit of detection of 50 copies/mL. Clinical laboratory evaluations for hematology, biochemistry, CD4/CD8, viral load and serology will be performed at the chest institute as per local practices. Fibroscan will be performed on a fasting patient. The probe transducer will be placed on the skin, between the rib bones at the level of the right lobe of the liver. An experienced operator (\> 500 examinations before the study), will perform the Fibroscan and the software will calculate the median . The standard M probe will be used in all patients. The XL probe will be used in obese patients (BMI\>30 Kg/m2) or if the M probe fails to provide accurate results. CAP examination will be performed at the same time to diagnose fatty liver. A valid Fibroscan result will be defined by 10 validated measures and IQR \< 30% of the median. The following cut-off values will be applied to diagnose fibrosis by Fibroscan: 1) 8 kilopascal (kPa) for significant liver fibrosis; 2) 13 kPa for cirrhosis. Fatty liver by CAP will be diagnosed with the following cut-off values: 1) 237.8 dB/m for mild steatosis; 2) 260 dB/m for moderate steatosis; 3) 292.3 dB/m for severe steatosis.
Subject Identification (ID) numbers will be assigned sequentially to each subject who is eligible to participate in the study. The Subject ID Number will consist of a three digit centre number and a three digit number according to chronological order of entry. If a patient discontinues from the study the Subject ID Number will not be reused. The Subject ID Numbers will be used for identification of subjects in the source documentation, and laboratory samples. This will ensure that subject data and laboratory samples leaving the study sites will be identified and tracked.
Randomization to study groups will be done using a computer-generated random allocation with stratification by gender. Summary statistics (mean, median, standard deviation, interquartile range) will be obtained for clinical and demographic data collected between baseline and study conclusion. The fatty liver and liver fibrosis scores by CAP and Fibroscan, respectively, at month 24 will be expressed as a function of exposure group, adjusting for baseline values of each outcome using an analysis of covariance (ANCOVA) model. The average difference in change of steatosis and fibrosis scores between the two groups and associated hypothesis tests will be obtained from the ANCOVA model. All analyses will be based on an intention-to-treat basis, that is, patients' data will be analyzed as randomized. To assess the sensitivity of inferences to missing data, we will generate plausible values for missing observations using multiple imputations (MI), which is a relatively objective methodology for handling missing data in longitudinal studies. In MI, multiple plausible values are generated for each missing item from the joint distribution of observed data using a Bayesian framework, and the results are pooled using established rules while simultaneously accounting for uncertainty in the imputation process. Multivariate logistic regression analysis will be used to explore factors associated with non-invasive diagnosis of fatty liver/NASH and significant liver fibrosis, including patient-related (age, gender, BMI), drug-induced (time on and type of cART), metabolic (diabetes, insulin resistance, lipid profile, hypertension), HIV-related (HIV viral load, CD4/CD8). Pearson correlation coefficient will be used to measure the association between CK-18 and Fibroscan/CAP values, BMI, transaminases. All hypotheses tests will be conducted at 5% level of significance (2-sided). Analyses will be performed using R program for Windows Release 2.13.1.
The trial will be monitored for safety and efficacy by a Data Safety Monitoring Board (DSMB) composed of clinicians, statisticians/methodologists and a lay member appointed by the McGill University Health center.
Adverse events (AEs) are defined as any untoward medical occurrence in a subject which does not necessarily have a causal relationship with the study medication/intervention. An AE can therefore be any unfavourable and unintended sign (including abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug/intervention, whether or not it is related to the medication/intervention.
Stable chronic conditions which are present prior to clinical study entry and do not worsen are not considered adverse events and will be accounted for in the subject's medical history.
Subjects who have an adverse event should be followed and treated by the Investigator until the abnormal parameter or symptom has resolved or stabilized. It is up to the clinician to determine that the AE is either resolved or that is has reached a stable state, after which no further follow-up is necessary. There should also be source documentation to support this determination. At each contact with the subject, information regarding adverse events will be elicited by appropriate questioning and examinations, and will be recorded immediately on a source document (e.g., progress notes, laboratory reports, survey tools, and data collection tools). The start date, stop date, severity of each reportable event, and the PI's judgment of the AE's relationship to the study, medication/intervention will also be recorded.
Any AE that occurs between baseline and 30 days following Week 24 (or at the time of early discontinuation of the subject from the study for any reason) is to be recorded in the source documentation (patient will be called). Surveillance for AEs will end at 30 days following Week 24. If an serious adverse event (SAE) is ongoing at the time a subject discontinues/completes the trial the SAE will be followed until the Investigator agrees that the event is satisfactorily resolved or that no further follow-up is required.
Virologic failure must be considered for any patient with plasma HIV RNA ≥50 c/mL at any time following randomization. For the purposes of clinical management in this study, virologic failure is defined as: Two consecutive plasma HIV RNA ≥50 c/mL within four weeks of the initial suspected virologic failure. Cases of confirmed virologic failure will trigger genotypic virologic resistance testing, including integrase resistance testing, when plasma HIV RNA \>400c/mL. The virologic failure definition is intended for guidance and Investigators should use their discretion as to the most appropriate clinical management of their patients. Due to the risk of developing integrase resistance in the setting of replicating HIV, change of antiretroviral therapy for subjects randomized to raltegravir is indicated for those with confirmed virologic failure. The choice of antiretroviral therapy will be left to the discretion of the treating physician.
The conduct of this study will conform to the International Conference for Harmonization and Good Clinical Practice (ICH-GCP) regulations and guidelines and the current revision of the Declaration of Helsinki A copy of the protocol (including protocol amendments), all versions of the informed consents, other information to be completed by subjects such as questionnaires, and any proposed advertising/ recruitment materials must be reviewed and approved by the research ethics board (REB) of each participating centre prior to implementation of the study. The investigator will be responsible for obtaining REB approval of the annual Continuing Review throughout the duration of the study. The investigator will notify the REB of violations from the protocol and SAEs.
All subjects will be given detailed oral and written information about the study. Consent forms describing in detail the study medications/intervention(s), study procedures, anticipated benefits and potential risks will be given to each participant and written documentation of informed consent is required prior to starting the study. Subjects must voluntarily sign and date an informed consent document that has been approved by the REB prior to any procedures being done specifically for the trial. Each subject should have sufficient opportunity to discuss the study and consider the information in the consent process prior to agreeing to participate. Subjects may withdraw consent at any time during the course of the trial. The informed consent will be signed and dated by the subject, the person who conducted the informed consent discussion and the investigator. The original signed informed consent form will be retained in the subject's study files and a copy will be provided to the subject.
All subject related information including the case report forms (CRFs), laboratory samples, evaluation forms, reports, etc. will be kept strictly confidential. All records will be kept in a secure, locked location and only research staff will have access to the records. Subjects will be identified only by means of a coded number specific to each subject, and a subject letter code. All computerized databases will identify subjects by numeric codes only, and will be password protected. Upon request, clinical information may be reviewed by or released to study monitors, auditors, Canadian Institutes of Health Research or regulatory agencies. The REB or other government organizations, as part of their duties to ensure that research subjects are protected may discontinue the study at any time. Regulatory authorities and the study Sponsor retain the authority to suspend additional enrollment for the entire study as applicable.
Data and study documents at all sites will be stored securely for 25 years, after which they will be destroyed in keeping with the privacy and confidentiality regulations and guidelines.
Appropriate medical and research records for this study and regulatory/ institutional requirements must be maintained for the protection of confidentiality of study subjects. The Principal Investigator is responsible for assuring that the data collected are complete, accurate, and recorded in a timely manner.
Once a candidate for screening has been identified, study details will be carefully discussed with the subject. The subject will be asked to read and sign the approved informed consent form prior to any assessments being performed. Self-administered questionnaires will collect information on Alcohol use and Disorders Identification Test (audit C), drug use. chart review, (demographics, medication medical history).
Blood samples will be obtained for clinical laboratory evaluations (as per standard of care) at baseline, and all follow-up visits, plus serum CK-18 that will be obtained at all follow-up visits. Routine hematology and chemistry evaluations will include: complete blood count (CBC) with differential, CD4 and CD8 cell counts, viral load, C-reactive Protein, D-dimer, and measurements of hepatic, pancreatic and renal function, fasting insulin, creatine kinase, glucose and lipid profiles. Plasma HIV RNA levels will be measured with a lower limit of detection of 50 copies/mL. Clinical laboratory evaluations for hematology, biochemistry, CD4/CD8, viral load and serology will be performed at the chest institute as per local practices. Fibroscan will be performed on a fasting patient. The probe transducer will be placed on the skin, between the rib bones at the level of the right lobe of the liver. An experienced operator (\> 500 examinations before the study), will perform the Fibroscan and the software will calculate the median . The standard M probe will be used in all patients. The XL probe will be used in obese patients (BMI\>30 Kg/m2) or if the M probe fails to provide accurate results. CAP examination will be performed at the same time to diagnose fatty liver. A valid Fibroscan result will be defined by 10 validated measures and IQR \< 30% of the median. The following cut-off values will be applied to diagnose fibrosis by Fibroscan: 1) 8 kilopascal (kPa) for significant liver fibrosis; 2) 13 kPa for cirrhosis. Fatty liver by CAP will be diagnosed with the following cut-off values: 1) 237.8 dB/m for mild steatosis; 2) 260 dB/m for moderate steatosis; 3) 292.3 dB/m for severe steatosis.
Subject Identification (ID) numbers will be assigned sequentially to each subject who is eligible to participate in the study. The Subject ID Number will consist of a three digit centre number and a three digit number according to chronological order of entry. If a patient discontinues from the study the Subject ID Number will not be reused. The Subject ID Numbers will be used for identification of subjects in the source documentation, and laboratory samples. This will ensure that subject data and laboratory samples leaving the study sites will be identified and tracked.
Randomization to study groups will be done using a computer-generated random allocation with stratification by gender. Summary statistics (mean, median, standard deviation, interquartile range) will be obtained for clinical and demographic data collected between baseline and study conclusion. The fatty liver and liver fibrosis scores by CAP and Fibroscan, respectively, at month 24 will be expressed as a function of exposure group, adjusting for baseline values of each outcome using an analysis of covariance (ANCOVA) model. The average difference in change of steatosis and fibrosis scores between the two groups and associated hypothesis tests will be obtained from the ANCOVA model. All analyses will be based on an intention-to-treat basis, that is, patients' data will be analyzed as randomized. To assess the sensitivity of inferences to missing data, we will generate plausible values for missing observations using multiple imputations (MI), which is a relatively objective methodology for handling missing data in longitudinal studies. In MI, multiple plausible values are generated for each missing item from the joint distribution of observed data using a Bayesian framework, and the results are pooled using established rules while simultaneously accounting for uncertainty in the imputation process. Multivariate logistic regression analysis will be used to explore factors associated with non-invasive diagnosis of fatty liver/NASH and significant liver fibrosis, including patient-related (age, gender, BMI), drug-induced (time on and type of cART), metabolic (diabetes, insulin resistance, lipid profile, hypertension), HIV-related (HIV viral load, CD4/CD8). Pearson correlation coefficient will be used to measure the association between CK-18 and Fibroscan/CAP values, BMI, transaminases. All hypotheses tests will be conducted at 5% level of significance (2-sided). Analyses will be performed using R program for Windows Release 2.13.1.
The trial will be monitored for safety and efficacy by a Data Safety Monitoring Board (DSMB) composed of clinicians, statisticians/methodologists and a lay member appointed by the McGill University Health center.
Adverse events (AEs) are defined as any untoward medical occurrence in a subject which does not necessarily have a causal relationship with the study medication/intervention. An AE can therefore be any unfavourable and unintended sign (including abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug/intervention, whether or not it is related to the medication/intervention.
Stable chronic conditions which are present prior to clinical study entry and do not worsen are not considered adverse events and will be accounted for in the subject's medical history.
Subjects who have an adverse event should be followed and treated by the Investigator until the abnormal parameter or symptom has resolved or stabilized. It is up to the clinician to determine that the AE is either resolved or that is has reached a stable state, after which no further follow-up is necessary. There should also be source documentation to support this determination. At each contact with the subject, information regarding adverse events will be elicited by appropriate questioning and examinations, and will be recorded immediately on a source document (e.g., progress notes, laboratory reports, survey tools, and data collection tools). The start date, stop date, severity of each reportable event, and the PI's judgment of the AE's relationship to the study, medication/intervention will also be recorded.
Any AE that occurs between baseline and 30 days following Week 24 (or at the time of early discontinuation of the subject from the study for any reason) is to be recorded in the source documentation (patient will be called). Surveillance for AEs will end at 30 days following Week 24. If an serious adverse event (SAE) is ongoing at the time a subject discontinues/completes the trial the SAE will be followed until the Investigator agrees that the event is satisfactorily resolved or that no further follow-up is required.
Virologic failure must be considered for any patient with plasma HIV RNA ≥50 c/mL at any time following randomization. For the purposes of clinical management in this study, virologic failure is defined as: Two consecutive plasma HIV RNA ≥50 c/mL within four weeks of the initial suspected virologic failure. Cases of confirmed virologic failure will trigger genotypic virologic resistance testing, including integrase resistance testing, when plasma HIV RNA \>400c/mL. The virologic failure definition is intended for guidance and Investigators should use their discretion as to the most appropriate clinical management of their patients. Due to the risk of developing integrase resistance in the setting of replicating HIV, change of antiretroviral therapy for subjects randomized to raltegravir is indicated for those with confirmed virologic failure. The choice of antiretroviral therapy will be left to the discretion of the treating physician.
The conduct of this study will conform to the International Conference for Harmonization and Good Clinical Practice (ICH-GCP) regulations and guidelines and the current revision of the Declaration of Helsinki A copy of the protocol (including protocol amendments), all versions of the informed consents, other information to be completed by subjects such as questionnaires, and any proposed advertising/ recruitment materials must be reviewed and approved by the research ethics board (REB) of each participating centre prior to implementation of the study. The investigator will be responsible for obtaining REB approval of the annual Continuing Review throughout the duration of the study. The investigator will notify the REB of violations from the protocol and SAEs.
All subjects will be given detailed oral and written information about the study. Consent forms describing in detail the study medications/intervention(s), study procedures, anticipated benefits and potential risks will be given to each participant and written documentation of informed consent is required prior to starting the study. Subjects must voluntarily sign and date an informed consent document that has been approved by the REB prior to any procedures being done specifically for the trial. Each subject should have sufficient opportunity to discuss the study and consider the information in the consent process prior to agreeing to participate. Subjects may withdraw consent at any time during the course of the trial. The informed consent will be signed and dated by the subject, the person who conducted the informed consent discussion and the investigator. The original signed informed consent form will be retained in the subject's study files and a copy will be provided to the subject.
All subject related information including the case report forms (CRFs), laboratory samples, evaluation forms, reports, etc. will be kept strictly confidential. All records will be kept in a secure, locked location and only research staff will have access to the records. Subjects will be identified only by means of a coded number specific to each subject, and a subject letter code. All computerized databases will identify subjects by numeric codes only, and will be password protected. Upon request, clinical information may be reviewed by or released to study monitors, auditors, Canadian Institutes of Health Research or regulatory agencies. The REB or other government organizations, as part of their duties to ensure that research subjects are protected may discontinue the study at any time. Regulatory authorities and the study Sponsor retain the authority to suspend additional enrollment for the entire study as applicable.
Data and study documents at all sites will be stored securely for 25 years, after which they will be destroyed in keeping with the privacy and confidentiality regulations and guidelines.
Appropriate medical and research records for this study and regulatory/ institutional requirements must be maintained for the protection of confidentiality of study subjects. The Principal Investigator is responsible for assuring that the data collected are complete, accurate, and recorded in a timely manner.
Detailed Description:
None
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?: