Ignite Creation Date:
2024-05-06 @ 12:12 PM
Last Modification Date:
2024-10-26 @ 12:56 PM
Study NCT ID:
NCT03706885
Status:
COMPLETED
Last Update Posted:
2023-02-15
First Post:
2018-08-15
Brief Title:
Efavirenz for Patients With Alzheimers Disease
Sponsor:
Case Western Reserve University
Organization:
Case Western Reserve University
Study Overview
Official Title:
A Proof-of-Concept Clinical Research Study of Efavirenz in Patients With Alzheimers Disease
Status:
COMPLETED
Status Verified Date:
2023-02
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:
EPAD
Brief Summary:
This will be a two-center placebo controlled blinded clinical trial to evaluate the safety and tolerability of efavirenz EFV in 36 clinically stable subjects with mild cognitive impairmentearly dementia due to Alzheimers Disease AD age 55 years Of these 36 total subjects 18 will be recruited by MGH and 18 will be recruited by UH A subset of the subjects at MGH only will also participate in a Stable Isotope Labeling Kinetics SILK protocol with deuterated water a nonhazardous substance designed to more precisely measure EFV effects on CNS cholesterol turnover
Each respective sites 18 total recruited individuals will be divided into 3 groups these 3 groups will represent two particular dosages of EFV and a placebo group respectively In a double-blind fashion participants will be receiving either a capsule of EFV or placebo daily for 20 weeks At MGH only 12 individuals 4 from each of the two EFV groups and placebo will participate in the unique heavy water SILK protocol assessing the kinetics of deuterium enrichment in plasma 24-hydroxycholesterol 24-OHC All study participants at both sites will have their blood cerebral spinal fluid and urine analyzed at various points throughout the study All participants will have their DNA genotyped for APOE isoforms E2 E3 or E4 and single nucleotide polymorphisms SNPs in CYP46A1 rs754203 and CYP2B6 rs3745274 to be used for post-hoc analysis
Each respective sites 18 total recruited individuals will be divided into 3 groups these 3 groups will represent two particular dosages of EFV and a placebo group respectively In a double-blind fashion participants will be receiving either a capsule of EFV or placebo daily for 20 weeks At MGH only 12 individuals 4 from each of the two EFV groups and placebo will participate in the unique heavy water SILK protocol assessing the kinetics of deuterium enrichment in plasma 24-hydroxycholesterol 24-OHC All study participants at both sites will have their blood cerebral spinal fluid and urine analyzed at various points throughout the study All participants will have their DNA genotyped for APOE isoforms E2 E3 or E4 and single nucleotide polymorphisms SNPs in CYP46A1 rs754203 and CYP2B6 rs3745274 to be used for post-hoc analysis
Detailed Description:
10 BACKGROUND
11 Introduction
The brain is the most cholesterol-rich organ in the body Circulating peripheral cholesterol cannot cross the blood-brain barrier and enter the brain so all of cerebral cholesterol is synthesized and metabolized locally The CNS relies on cholesterol 24-hydroxylation as its major mechanism for eliminating excess cholesterol from the brain CYP46A1 is an enzyme of the CNS responsible for hydroxylating cholesterol to 24-hydroxycholesterol 24-OHC which can easily pass the blood-brain barrier and leave the brain to travel into the systemic blood circulation In fact 24-OHC plasma level is a specific biomarker for cholesterol homeostasis and CYP46A1 activity in the brain 24-OHC is a potent modulator of NMDAR a receptor system in the brain whose hypofunctioning can lead to problems of memory and learning performance Cyp46a1-- mice and CYP46A1 transgenic animals established that CYP46A1 is involved in higher-order brain functions and processes beyond mere cholesterol balance the Cyp46a1-- mice lacking CYP46A1 demonstrated severe deficiencies in spatial associative and motor learning-- as well as deficiencies in long-term potentiation of the hippocampus On the other hand CYP46A1 transgenic animals with an abundance of CYP46A1 had improvements in spatial memory and significant increase in the levels of NMDAR in the hippocampus CYP46A1 overexpressing mice possessing an animal model of AD demonstrated improvements in learning and memory and reduction in pathological amyloid beta
Various studies have demonstrated a number of associations between CYP46A1 and AD For unknown reasons this neuron-specific enzyme becomes specifically expressed in astrocytes of AD patients plasma levels of 24-OHC the product of CYP46A1 also change in AD patients-there are slight elevations of plasma levels in the early stages of AD followed by decreases in the later stages of AD the elevations have been interpreted to represent demyelination of the brain and subsequent release of 24-OHC into the systemic circulation and the decreases could be attributed to loss of CYP46A1 during the physical process of neuronal degeneration and finally CYP46A1 is highly polymorphic enzyme with the most frequent intronic SNPs rs754203 rs3742376 rs7157609 and rs4900442 being found at 29- 40 frequency in the population The CYP46A1-AD genetic link is however unclear with only about half of linkage studies establishing the CYP46A1-AD association Data from several laboratories point to enhanced metabolism of cerebral cholesterol as a strong anti-AD disease mechanism
CYP46A1-mediated metabolism of cerebral cholesterol has never been considered as a pharmacologic target because the proposed activity requires activation of the enzyme a significant challenge for drug developers Only 5 of drugs on the market act as enzyme activators with the majority of pharmaceuticals serving as enzyme inhibitors Dr Pikulevas laboratory--over the course of more than 10 years work--overcame this challenge by ultimately discovering that in mice CYP46A1 can indeed be activated pharmacologically by efavirenz EFV This CYP46A1 activation also leads to enhanced cerebral cholesterol turnover in mice
20 STUDY RATIONALE
AD has been shown to be a disease featuring rampant aberrant cerebral cholesterol phenomenon hence the AD population is the most appropriate demographic to include in this study The investigators expect EFV to be a cerebral cholesterol-metabolism-modifying medication which may have prolific uses in neurodegenerative diseases--such as AD--where cholesterol metabolism is aberrant
21 RiskBenefit Assessment
EFV is an FDA-approved anti-retroviral medication for use in the adult population-including the geriatric population The current recommended dose of Sustiva for adults with HIV is 600 mg daily This research study will be utilizing very low doses of Sustiva 50 mg and 200 mg which are the current dosage ranges for children The investigators have no reason to believe that utilizing 13 the adult dose of a drug in the geriatric population will increase the risk of the drug beyond those side effects which are already listed for this product The study participants will be monitored very closely throughout the course of the research study to bring to light any untoward effects in the participants that would outweigh the potential benefit of this study
30 STUDY OBJECTIVES
31 Primary Objectives
To ascertain if EFV engages CYP46A1 and affects brain cholesterol metabolism
To investigate whether EFV alters plasma 24-OHC concentrations
To confirm the safety and tolerability of low doses of EFV
32 Secondary Objectives
To precisely measure EFVs effect on CYP46A1 activation and CNS-cholesterol turnover via Stable Isotope Labeling Kinetics SILK study
33 Tertiary Objectives
To conduct post-hoc analysis to investigate whether APOE isorforms and SNPs in CYP46A1 and CYP2B6 affect study participant response to EFV
40 STUDY DESIGN
41 Study Design Overview
A total of 36 patients will be enrolled at 2 sites 18 patients at the UH site and 18 patients at the MGH site Site UH the recruiting clinician at this site is Alan Lerner MD Site MGH recruiting clinician at this site is Steven Arnold MD At each site subjects will be divided into 3 groups Group1 will consist of 6 subjects who will receive 50 mg EFV Group 2 will consist of 6 subjects who will receive 200 mg EFV and Group 3 will consist of 6 subjects who will receive Placebo
50 CRITERIA FOR EVALUATIONS
51 Primary Endpoints
CYP46A1 engagement will be indicated either by a decrease or increase in plasma 24-OHC from baseline to final time of treatment in the study participants receiving EFV
CYP46A1 activation will be indicated by 30 increase in plasma 24-OHC from baseline to final time of treatment in the study participants receiving EFV The primary dose selection criterion for EFV will be to maximize the proportion of subjects that exceed the threshold for 24-OHC increase provided there are no associated safety concerns
A symptom checklist will be reviewed and asked of the study participants every two weeks to ensure that no untoward serious complications arise from treatment with EFV It is not expected that any serious adverse events will occur All participants will conclude their treatment with a Post-Study Safety Check Visit during Week 22
52 Secondary Endpoints
Plasma levels of deuterated 24-OHC in patients involved in the SILK study who will drink deuterated water will be measured to evaluate EFVs effect on CNS-cholesterol turnover
53 Tertiary Endpoints
Carriers of the APOE E4 allele could be better responders to the anti-AD effects of EFV because in the brain cholesterol output is a function of both APOE-mediated cholesterol transport and CYP46A1-mediated cholesterol metabolism Accordingly if one of these pathways is impaired like in APOE E4 carriers the significance of the other pathway is increased Similarly the CYP46A1 polymorphisms may affect the ability of EFV to increase 24-OHC because the baseline levels of CYP46A1 and 24-OHC in the carriers of these polymorphisms could be lower if these polymorphisms affect CYP46A1 protein levels Finally at a high dose 400-600 mgday plasma concentrations of EFV depend on the frequent SNP rs3745274 in CYP2B6 that metabolizes EFV Genotyping will be carried out by the Molecular Biology and Genotyping Module at Case Western Reserve University
60 SUBJECT SELECTION
A total of 36 participants either male or female will be enrolled between the ages of 55-85 for 22 weeks Recruitment of study participants will occur during potential participants regularly-schedule clinical visits or from chart review
61 Study Population
All participants should have either mild cognitive impairment or early dementia due to AD defined clinically as follows
Complaint of cognitive decline
Mini-Mental Status Examination MMSE totaling between 16-30
Clinical Dementia Rating CDR equaling 05-1
The 36 study participants will be recruited in a timeframe of approximately 8-9 months The two study sites are anticipated to recruit 2 study participants per month This anticipated rate is based on the investigators previous experience in clinical study subject enrollment and high patient volume at the University Hospitals Brain Health and Memory Center and the Memory Disorders Clinic and the Memory Disorders Unit and Massachusetts Alzheimers Disease Research Center MADRC at Massachusetts General Hospitals MGH
70 CONCOMITANT THERAPIES
Medical history will be collected for all medications at the screening visit and at all subsequent clinical and telephone follow-up visits All subjects should be maintained on the same medications from screening through Visit 7 as medically feasible with no introduction of new therapiesIf any changes in concomitant medications are made for any reason by the study participants personal physicians the changes and reasons for the changes will be documented
71 Allowed
Except as noted in the prohibited medications section 72 Stable use of cholinesterase inhibitor is permitted if doses are stable for 3 months prior to enrollment
72 Prohibited
EFV is mainly metabolized by CYP2B6 and CYP3A4 and in the 600 mgday dose range or higher has potential interactions with other drugs EFV is expected to stimulate cholesterol elimination from the brain inducing a compensatory upregulation of cerebral cholesterol biosynthesis statins that cross the blood-brain barrier would be expected to especially inhibit cerebral cholesterol biosynthesis and confound 24-OHC biomarking of EFVs effect Study participants in the clinical research study should not have taken the following medication within 3 months of commencing their participatory role in the study simvastatin antiepileptic agents clopidogrel voriconazole systemic ketoconazole cyclosporine St Johns Wort
11 Introduction
The brain is the most cholesterol-rich organ in the body Circulating peripheral cholesterol cannot cross the blood-brain barrier and enter the brain so all of cerebral cholesterol is synthesized and metabolized locally The CNS relies on cholesterol 24-hydroxylation as its major mechanism for eliminating excess cholesterol from the brain CYP46A1 is an enzyme of the CNS responsible for hydroxylating cholesterol to 24-hydroxycholesterol 24-OHC which can easily pass the blood-brain barrier and leave the brain to travel into the systemic blood circulation In fact 24-OHC plasma level is a specific biomarker for cholesterol homeostasis and CYP46A1 activity in the brain 24-OHC is a potent modulator of NMDAR a receptor system in the brain whose hypofunctioning can lead to problems of memory and learning performance Cyp46a1-- mice and CYP46A1 transgenic animals established that CYP46A1 is involved in higher-order brain functions and processes beyond mere cholesterol balance the Cyp46a1-- mice lacking CYP46A1 demonstrated severe deficiencies in spatial associative and motor learning-- as well as deficiencies in long-term potentiation of the hippocampus On the other hand CYP46A1 transgenic animals with an abundance of CYP46A1 had improvements in spatial memory and significant increase in the levels of NMDAR in the hippocampus CYP46A1 overexpressing mice possessing an animal model of AD demonstrated improvements in learning and memory and reduction in pathological amyloid beta
Various studies have demonstrated a number of associations between CYP46A1 and AD For unknown reasons this neuron-specific enzyme becomes specifically expressed in astrocytes of AD patients plasma levels of 24-OHC the product of CYP46A1 also change in AD patients-there are slight elevations of plasma levels in the early stages of AD followed by decreases in the later stages of AD the elevations have been interpreted to represent demyelination of the brain and subsequent release of 24-OHC into the systemic circulation and the decreases could be attributed to loss of CYP46A1 during the physical process of neuronal degeneration and finally CYP46A1 is highly polymorphic enzyme with the most frequent intronic SNPs rs754203 rs3742376 rs7157609 and rs4900442 being found at 29- 40 frequency in the population The CYP46A1-AD genetic link is however unclear with only about half of linkage studies establishing the CYP46A1-AD association Data from several laboratories point to enhanced metabolism of cerebral cholesterol as a strong anti-AD disease mechanism
CYP46A1-mediated metabolism of cerebral cholesterol has never been considered as a pharmacologic target because the proposed activity requires activation of the enzyme a significant challenge for drug developers Only 5 of drugs on the market act as enzyme activators with the majority of pharmaceuticals serving as enzyme inhibitors Dr Pikulevas laboratory--over the course of more than 10 years work--overcame this challenge by ultimately discovering that in mice CYP46A1 can indeed be activated pharmacologically by efavirenz EFV This CYP46A1 activation also leads to enhanced cerebral cholesterol turnover in mice
20 STUDY RATIONALE
AD has been shown to be a disease featuring rampant aberrant cerebral cholesterol phenomenon hence the AD population is the most appropriate demographic to include in this study The investigators expect EFV to be a cerebral cholesterol-metabolism-modifying medication which may have prolific uses in neurodegenerative diseases--such as AD--where cholesterol metabolism is aberrant
21 RiskBenefit Assessment
EFV is an FDA-approved anti-retroviral medication for use in the adult population-including the geriatric population The current recommended dose of Sustiva for adults with HIV is 600 mg daily This research study will be utilizing very low doses of Sustiva 50 mg and 200 mg which are the current dosage ranges for children The investigators have no reason to believe that utilizing 13 the adult dose of a drug in the geriatric population will increase the risk of the drug beyond those side effects which are already listed for this product The study participants will be monitored very closely throughout the course of the research study to bring to light any untoward effects in the participants that would outweigh the potential benefit of this study
30 STUDY OBJECTIVES
31 Primary Objectives
To ascertain if EFV engages CYP46A1 and affects brain cholesterol metabolism
To investigate whether EFV alters plasma 24-OHC concentrations
To confirm the safety and tolerability of low doses of EFV
32 Secondary Objectives
To precisely measure EFVs effect on CYP46A1 activation and CNS-cholesterol turnover via Stable Isotope Labeling Kinetics SILK study
33 Tertiary Objectives
To conduct post-hoc analysis to investigate whether APOE isorforms and SNPs in CYP46A1 and CYP2B6 affect study participant response to EFV
40 STUDY DESIGN
41 Study Design Overview
A total of 36 patients will be enrolled at 2 sites 18 patients at the UH site and 18 patients at the MGH site Site UH the recruiting clinician at this site is Alan Lerner MD Site MGH recruiting clinician at this site is Steven Arnold MD At each site subjects will be divided into 3 groups Group1 will consist of 6 subjects who will receive 50 mg EFV Group 2 will consist of 6 subjects who will receive 200 mg EFV and Group 3 will consist of 6 subjects who will receive Placebo
50 CRITERIA FOR EVALUATIONS
51 Primary Endpoints
CYP46A1 engagement will be indicated either by a decrease or increase in plasma 24-OHC from baseline to final time of treatment in the study participants receiving EFV
CYP46A1 activation will be indicated by 30 increase in plasma 24-OHC from baseline to final time of treatment in the study participants receiving EFV The primary dose selection criterion for EFV will be to maximize the proportion of subjects that exceed the threshold for 24-OHC increase provided there are no associated safety concerns
A symptom checklist will be reviewed and asked of the study participants every two weeks to ensure that no untoward serious complications arise from treatment with EFV It is not expected that any serious adverse events will occur All participants will conclude their treatment with a Post-Study Safety Check Visit during Week 22
52 Secondary Endpoints
Plasma levels of deuterated 24-OHC in patients involved in the SILK study who will drink deuterated water will be measured to evaluate EFVs effect on CNS-cholesterol turnover
53 Tertiary Endpoints
Carriers of the APOE E4 allele could be better responders to the anti-AD effects of EFV because in the brain cholesterol output is a function of both APOE-mediated cholesterol transport and CYP46A1-mediated cholesterol metabolism Accordingly if one of these pathways is impaired like in APOE E4 carriers the significance of the other pathway is increased Similarly the CYP46A1 polymorphisms may affect the ability of EFV to increase 24-OHC because the baseline levels of CYP46A1 and 24-OHC in the carriers of these polymorphisms could be lower if these polymorphisms affect CYP46A1 protein levels Finally at a high dose 400-600 mgday plasma concentrations of EFV depend on the frequent SNP rs3745274 in CYP2B6 that metabolizes EFV Genotyping will be carried out by the Molecular Biology and Genotyping Module at Case Western Reserve University
60 SUBJECT SELECTION
A total of 36 participants either male or female will be enrolled between the ages of 55-85 for 22 weeks Recruitment of study participants will occur during potential participants regularly-schedule clinical visits or from chart review
61 Study Population
All participants should have either mild cognitive impairment or early dementia due to AD defined clinically as follows
Complaint of cognitive decline
Mini-Mental Status Examination MMSE totaling between 16-30
Clinical Dementia Rating CDR equaling 05-1
The 36 study participants will be recruited in a timeframe of approximately 8-9 months The two study sites are anticipated to recruit 2 study participants per month This anticipated rate is based on the investigators previous experience in clinical study subject enrollment and high patient volume at the University Hospitals Brain Health and Memory Center and the Memory Disorders Clinic and the Memory Disorders Unit and Massachusetts Alzheimers Disease Research Center MADRC at Massachusetts General Hospitals MGH
70 CONCOMITANT THERAPIES
Medical history will be collected for all medications at the screening visit and at all subsequent clinical and telephone follow-up visits All subjects should be maintained on the same medications from screening through Visit 7 as medically feasible with no introduction of new therapiesIf any changes in concomitant medications are made for any reason by the study participants personal physicians the changes and reasons for the changes will be documented
71 Allowed
Except as noted in the prohibited medications section 72 Stable use of cholinesterase inhibitor is permitted if doses are stable for 3 months prior to enrollment
72 Prohibited
EFV is mainly metabolized by CYP2B6 and CYP3A4 and in the 600 mgday dose range or higher has potential interactions with other drugs EFV is expected to stimulate cholesterol elimination from the brain inducing a compensatory upregulation of cerebral cholesterol biosynthesis statins that cross the blood-brain barrier would be expected to especially inhibit cerebral cholesterol biosynthesis and confound 24-OHC biomarking of EFVs effect Study participants in the clinical research study should not have taken the following medication within 3 months of commencing their participatory role in the study simvastatin antiepileptic agents clopidogrel voriconazole systemic ketoconazole cyclosporine St Johns Wort
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
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