Ignite Creation Date:
2024-05-06 @ 4:15 PM
Last Modification Date:
2024-10-26 @ 2:07 PM
Study NCT ID:
NCT04928963
Status:
UNKNOWN
Last Update Posted:
2021-10-25
First Post:
2021-06-11
Brief Title:
Fighting Immunosenescence and Promoting Immunity by a Fasting-mimicking Diet Elderly
Sponsor:
University of Genova
Organization:
University of Genova
Study Overview
Official Title:
Phase III Randomized Clinical Study of Cycles of a New Formulated FMD in Prefrail Elderly
Status:
UNKNOWN
Status Verified Date:
2021-10
Last Known Status:
RECRUITING
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:
Background Immunosenescence is an aging-dependent phenomenon underlying age dependent deterioration in the function of the immune system characterized by a decline in B and T cells with a relative increase in natural killer NK cells Aging also promotes chronic inflammation accompanied by increased levels of pro-inflammatory cytokines Both immunosenescence and inflammation contribute to frailty which is a geriatric syndrome characterized by age-related deterioration in multiple physiological systems resulting in greater vulnerability to stressors and increased risk of poor outcomes including longer hospital stays postoperative complications poor responses to vaccination functional decline and death
Although pharmacological interventions could be developed to address immunosenescence inflammation and frailty a dietary intervention that does not cause weight or muscle loss may be a preferable option particularly if it is periodic in nature and it only needs to be adopted for a few weeks per year
Hypothesis We will test the hypothesis that a newly formulated and relatively high calorie fasting mimicking diet FMD to be administered to subjects age 65-80 once a month for 5 days for two to six cycles can partially reverse immunosenescence and inflammation thus contributing to the reduction of frailty
Aims This proposal is divided into 2 main tasks
Task 1 We will determine whether FMD cycles in mice a prevent frailty syndrome onset and symptoms B delay or reverse age-related immunosenescence and inflammaging C improve the functionality of bone marrow cells D enhances the response to flu vaccination Task 2 A We will develop a special relatively high calorie FMD medical food for testing in humans B We will test the safety and efficacy of the FMD medical food in an aged and frail individuals 65-80 yr for 2-5 day cycles preceding their annual influenza vaccination Expected results In mice we expect that the FMD diet will reduce the clinical signs of frailty during aging and in particular increase immune system influenza vaccine response by preventing immunesenescence We expect that the FMD will reduce phosphorylation of mTOR and of its downstream targets and induce autophagy and apoptosis in WBCs These effects are anticipated to remove damaged cells and promote the activation of hematopoietic stem cells and the generation of new WBCs We also expect that the transient increase in corticosteroids and removal of damage immune cells will be accompanied by a decrease in systemic inflammation Increased performance on rotarod and other measures of frailty is also anticipated In humans we expect that the FMD will be well tolerated by the pre-frail elderly without major adverse events and that it will be possible to achieve high compliance to this diet We also anticipate that elderly undergoing the FMD protocol followed by 30 days of a normal diet plus supplements will exhibit better functional status and better response to the flu vaccine as compared to patients from the control arm An improvement in handgrip strength and in lean body mass as detected by BIA is also expected at least in a fraction of the patients from the intervention arm Impact Frailty is a geriatric syndrome characterized by age-related deterioration in multiple physiological systems and homeostatic mechanisms resulting in greater vulnerability to stressors and increased risk of poor outcomes including longer hospital stays postoperative complications poor responses to vaccination functional decline and death Thus the identification of a dietary strategy potentially to be applied for only 10 days a year but able to rejuvenate the immune profile and function while reducing systemic inflammation could have a major impact on both healthspan and health-related expenses Because older individuals are often taking multiple drugs the dietary intervention being investigated here would also reduce the potential toxicity of an additional pharmacological intervention
Although pharmacological interventions could be developed to address immunosenescence inflammation and frailty a dietary intervention that does not cause weight or muscle loss may be a preferable option particularly if it is periodic in nature and it only needs to be adopted for a few weeks per year
Hypothesis We will test the hypothesis that a newly formulated and relatively high calorie fasting mimicking diet FMD to be administered to subjects age 65-80 once a month for 5 days for two to six cycles can partially reverse immunosenescence and inflammation thus contributing to the reduction of frailty
Aims This proposal is divided into 2 main tasks
Task 1 We will determine whether FMD cycles in mice a prevent frailty syndrome onset and symptoms B delay or reverse age-related immunosenescence and inflammaging C improve the functionality of bone marrow cells D enhances the response to flu vaccination Task 2 A We will develop a special relatively high calorie FMD medical food for testing in humans B We will test the safety and efficacy of the FMD medical food in an aged and frail individuals 65-80 yr for 2-5 day cycles preceding their annual influenza vaccination Expected results In mice we expect that the FMD diet will reduce the clinical signs of frailty during aging and in particular increase immune system influenza vaccine response by preventing immunesenescence We expect that the FMD will reduce phosphorylation of mTOR and of its downstream targets and induce autophagy and apoptosis in WBCs These effects are anticipated to remove damaged cells and promote the activation of hematopoietic stem cells and the generation of new WBCs We also expect that the transient increase in corticosteroids and removal of damage immune cells will be accompanied by a decrease in systemic inflammation Increased performance on rotarod and other measures of frailty is also anticipated In humans we expect that the FMD will be well tolerated by the pre-frail elderly without major adverse events and that it will be possible to achieve high compliance to this diet We also anticipate that elderly undergoing the FMD protocol followed by 30 days of a normal diet plus supplements will exhibit better functional status and better response to the flu vaccine as compared to patients from the control arm An improvement in handgrip strength and in lean body mass as detected by BIA is also expected at least in a fraction of the patients from the intervention arm Impact Frailty is a geriatric syndrome characterized by age-related deterioration in multiple physiological systems and homeostatic mechanisms resulting in greater vulnerability to stressors and increased risk of poor outcomes including longer hospital stays postoperative complications poor responses to vaccination functional decline and death Thus the identification of a dietary strategy potentially to be applied for only 10 days a year but able to rejuvenate the immune profile and function while reducing systemic inflammation could have a major impact on both healthspan and health-related expenses Because older individuals are often taking multiple drugs the dietary intervention being investigated here would also reduce the potential toxicity of an additional pharmacological intervention
Detailed Description:
A phase III randomized clinical study will be performed to assess feasibility safety and efficacy improvement of the response to vaccination but also functional status improvement or maintenance of two cycles of FMD 1 week administered 30 days apart preceding flu vaccination in pre-frail elderly subjects The study will enrol 40 pre-frail subjects aged 65-80 years Subjects will be excluded if they have known immunosuppressive disorders or medications or have not received influenza vaccination in the previous two years Subjects will be randomized 11 to Arm A FMD or Arm B regular diet Subjects in Arm A will receive the 5 day FMD diet once a month for 2 months 2 cycles completed in 40 days 5-30-5
This is based on the regimen adopted in our ongoing study with younger subjects but involves one less cycle to minimize weight loss and other potential side effects in elderly subjects The primary endpoint will be diet safety the side effects of the diet will be assessed by weight change headaches blood pressure and by closely monitoring body composition ie lean body mass by bio-impedance measurements handgrip strength and DEXA scans The secondary endpoints will include i the compliance with the FMD ii the improvement of frailty parameters and prevention of disability in patients 65-80 years of age iii the improvement in immune parameters after 2 cycles of the diet and will be based on measures of improved T cell response reduced inflammation improved lymphoidmyeloid ratios and HSCpre-HSC number improved B cell numbers and CSR iv the efficacy of the influenza vaccine assayed by higher antibody titer levels In addition we will also document the number of flu episodes over the course of the trial The trial will be carried out over a period of 3 years and all subjects will be vaccinated in the fall of each year with the current preparation of the inactivated virus influenza vaccine Fluzone high dose Sanofi Pasteur Inc at the San Martino Hospital During the flu season each participant will receive weekly reminders to call in and report any influenza like symptoms These will include respiratory symptoms cough sore throat shortness of breath and nasal stuffiness and systemic symptoms headache malaise fatigue fever or feverishness and muscle aches Flu-like illnesses will be documented based on the report of two respiratory symptoms or one respiratory and one systemic symptom when influenza is known to be circulating in the local community A laboratory diagnosis of influenza illness will be confirmed from the results of nasopharyngeal swabs for virus culture andor a pre- to post-illness 4-fold or greater rise in antibody titer Blood samples will be collected at baseline after 2 diet cycles prior to vaccination and at 4 weeks after vaccination The study period for this trial will be 2-5 day diet cycles 5-30-5 followed by a single flu vaccination per year Each diet cycle will consist of 5 days of FMD followed by 30 days of the subjects usual diet plus a plant-based daily protein and fat supplement 20 grams of proteins 30 grams of olive oil and 30 grams total of walnuts hazelnuts and almonds This daily supplement serves at minimizing weight loss caused by the 5 day FMD At the first visit subjects will undergo a physical evaluation to assess health and frailty status and medical history will be noted Blood samples will be collected for baseline measurements
Subjects in the FMD arm will be given a 2 cycle supply of the diet with instructions Before receiving the second FMD cycle patients will undergo a second physical examination at the geriatrics Clinic of the University of Genoa which will include the assessment of body composition and the administration of the second FMD cycle will only be allowed in the absence of a decrease in lean body mass vs baseline as detected by BIA handgrip strenght and by DEXA Two weeks after completion of second diet cycle subjects will return for physical evaluation blood collection and vaccination The third and final visit will be 4 weeks following vaccination the subjects will undergo a physical evaluation and assessment of body composition and blood samples will be collected At this visit subjects will also be instructed to call the research coordinator to report malaise discomfort influenza or respiratory symptoms Further follow-up will be over the phone to monitor onset of influenza Nasopharyngeal swabs for virus culture and confirmation of influenza will be collected if possible within 72 hours of a subject reporting symptoms of influenza DIET Subjects randomized to the restricted diet arm A will be provided with all food to be consumed during each of the three cycles The exact components of the diet will depend on results obtained in Task
1 but the diet is anticipated to be approximately 30 calorie restricted and 50 protein restricted but supplemented with 50 of the RDA in vitamins and minerals and also supplemented with both nonessential and essential amino acids identified in animal studies to be effective Amino acid supplementation levels will depend on published clinical studies demonstrating safety and will not exceed the recommended daily levels Subjects in the control arm will receive dietary advice per the standard practice of the treating physician This will include consultation with a registered dietitian A major focus will be placed on ensuring that subjects do not lose weight unless obese at baseline nor lose lean body mass They will also be asked to maintain a diary of the food consumed and approximate amounts
VACCINATION Subjects will be vaccinated with the standard dose of the Fluzone high dose vaccine from Sanofi Pasteur Inc for each year This vaccine has four times the normal antigen contained in the regular flu vaccine and is specially designed for individuals 60 and older
Criteria for Removal from Study
Subjects will be removed from the study if they do not receive the vaccination Subjects will be removed from study if they have unacceptable toxicity related to the diet
Subjects will be removed from study is they are unable to regain at least 95 of their body weight after the first and 92 after the second cycle Subjects will be removed from study in the presence of a decrease in bioimpedance phase angle exceeding 5 of the baseline value or whenever the phase angle will drop below 5 or alternatively in those patients in which bioimpedance measurements were unreliableunattainable in the presence of a decrease in handgrip strength or in lean body mass detected by DEXA 5 of the baseline value Subjects may voluntarily withdraw from the study at any time for any reason STUDY OBSERVATIONS Visit 1 A complete medical history will be documented at the first visit at the San Martino Hospital Prof
P Odetti MD Prof A Nencioni This will include documentation of chronic diseases and any diseases that could increase risk for influenza including congestive heart failure ischemic heart disease chronic lung disease diabetes kidney failure neoplastic disorders and immune dysfunction weight and performance status All medications will be recorded A physical will be performed and Body Mass Index BMI and body composition will be determined and must be within inclusion parameters Pre-frailty will be diagnosed in participant whether one or two of Fried modified criteria for frailty will be present A blood draw will be performed Baseline laboratory measurements will include a CBC glucose ketone bodies insulin IGF-I IGFBP-1 cytokine panel lymphoidmyeloid ratio CD4CD8 ratio naïve memory T cells ratio and CD8CD28 T cells To assess humoral immunity percentages and absolute numbers of CD19 B cells naïve IgM memory and switch memory B cells will be assessed Briefly PBMCs isolated from whole blood will be enriched for CD19 B cells using anti-CD19 Microbeads Miltenyi Biotech To isolate naïve memory and switch memory cells CD19 cells will be sorted using a flow cytometer after staining with PE-conjugated anti-CD27 biotin-SP-conjugated ChromPure human IgG and 20 μl biotin-SPconjugated ChromPure human IgA To detect CSR in vitro CD19 B cells will be cultured with anti CD40 and IL-4 for 6-7 days AID expression in the stimulated B cells will be measured by RT-PCR E47 expression will be measured by western blot Visit 2 Subjects will return to the clinic upon completion of one cycle of the diet The participants will be subjected to a new medical examination to evaluate their physical activity neuropsychological and to determine the frailty index In addition they will also undergo a body composition assessment by bioimpedance measurement by DEXA scan and by handgrip strength A blood draw will be performed
Laboratory values will include all measurements as above to assess post-diet changes in all the parameters described above Visit 3 two weeks after the second FMD cycle same as in visit 2 In addition all subjects will receive a single injection of influenza vaccination Visit 4 Subjects will return at 4 weeks post vaccination when antibody titers are expected to peak We will perform the clinical examinations and the body composition assessments performed on previous visits on the participants Laboratory measurements will be as above In addition antibody titers in serum will be measured by the haemagglutination inhibition assay Hemagglutinin for each virus strain will be obtained from the CDC stock 2 fold dilutions of serum from 110 to 11024 will be used Chronic agerelated muscle loss affects 30 of individuals over 60 and 50 of individuals over 80 Insufficient protein intake in the elderly may promote loss in muscle mass by preventing muscle protein synthesis Thus bioimpedance measurements and whole body DEXA scans will be conducted in order to ensure that the diet does not cause loss in muscle mass Follow-up The subjects enrolled in the study will be called every three months after the fourth visit see above to undergo physical and psychological examinations in order to evaluate the FMD efficacy in preventing frailty reinforcing the immune system and increasing efficacy of influenza vaccine During the predicted influenza season in the local area subjects will receive weekly phone calls from the trial coordinator to document any symptoms and to remind them to call in to report symptoms If possible NP swabs will be collected within 72 hours of reporting of symptoms by having the RN travel to the subjects homes The incentive for participants to report symptoms early will be access to free diagnosis and referral to the primary physician for treatment of influenza illness Non-compliance will be defined as consumption of 50 of the prescribed diet andor consumption of 150 kcal non-prescribed food on any of the days of the FMD Results for subjects with less than a 50 reduction in IGF-I and 40 reduction in glucose compared to baseline will be analyzed intention-to-treat but a secondary analysis excluding these patients suspected of being non-compliant may be performed
This is based on the regimen adopted in our ongoing study with younger subjects but involves one less cycle to minimize weight loss and other potential side effects in elderly subjects The primary endpoint will be diet safety the side effects of the diet will be assessed by weight change headaches blood pressure and by closely monitoring body composition ie lean body mass by bio-impedance measurements handgrip strength and DEXA scans The secondary endpoints will include i the compliance with the FMD ii the improvement of frailty parameters and prevention of disability in patients 65-80 years of age iii the improvement in immune parameters after 2 cycles of the diet and will be based on measures of improved T cell response reduced inflammation improved lymphoidmyeloid ratios and HSCpre-HSC number improved B cell numbers and CSR iv the efficacy of the influenza vaccine assayed by higher antibody titer levels In addition we will also document the number of flu episodes over the course of the trial The trial will be carried out over a period of 3 years and all subjects will be vaccinated in the fall of each year with the current preparation of the inactivated virus influenza vaccine Fluzone high dose Sanofi Pasteur Inc at the San Martino Hospital During the flu season each participant will receive weekly reminders to call in and report any influenza like symptoms These will include respiratory symptoms cough sore throat shortness of breath and nasal stuffiness and systemic symptoms headache malaise fatigue fever or feverishness and muscle aches Flu-like illnesses will be documented based on the report of two respiratory symptoms or one respiratory and one systemic symptom when influenza is known to be circulating in the local community A laboratory diagnosis of influenza illness will be confirmed from the results of nasopharyngeal swabs for virus culture andor a pre- to post-illness 4-fold or greater rise in antibody titer Blood samples will be collected at baseline after 2 diet cycles prior to vaccination and at 4 weeks after vaccination The study period for this trial will be 2-5 day diet cycles 5-30-5 followed by a single flu vaccination per year Each diet cycle will consist of 5 days of FMD followed by 30 days of the subjects usual diet plus a plant-based daily protein and fat supplement 20 grams of proteins 30 grams of olive oil and 30 grams total of walnuts hazelnuts and almonds This daily supplement serves at minimizing weight loss caused by the 5 day FMD At the first visit subjects will undergo a physical evaluation to assess health and frailty status and medical history will be noted Blood samples will be collected for baseline measurements
Subjects in the FMD arm will be given a 2 cycle supply of the diet with instructions Before receiving the second FMD cycle patients will undergo a second physical examination at the geriatrics Clinic of the University of Genoa which will include the assessment of body composition and the administration of the second FMD cycle will only be allowed in the absence of a decrease in lean body mass vs baseline as detected by BIA handgrip strenght and by DEXA Two weeks after completion of second diet cycle subjects will return for physical evaluation blood collection and vaccination The third and final visit will be 4 weeks following vaccination the subjects will undergo a physical evaluation and assessment of body composition and blood samples will be collected At this visit subjects will also be instructed to call the research coordinator to report malaise discomfort influenza or respiratory symptoms Further follow-up will be over the phone to monitor onset of influenza Nasopharyngeal swabs for virus culture and confirmation of influenza will be collected if possible within 72 hours of a subject reporting symptoms of influenza DIET Subjects randomized to the restricted diet arm A will be provided with all food to be consumed during each of the three cycles The exact components of the diet will depend on results obtained in Task
1 but the diet is anticipated to be approximately 30 calorie restricted and 50 protein restricted but supplemented with 50 of the RDA in vitamins and minerals and also supplemented with both nonessential and essential amino acids identified in animal studies to be effective Amino acid supplementation levels will depend on published clinical studies demonstrating safety and will not exceed the recommended daily levels Subjects in the control arm will receive dietary advice per the standard practice of the treating physician This will include consultation with a registered dietitian A major focus will be placed on ensuring that subjects do not lose weight unless obese at baseline nor lose lean body mass They will also be asked to maintain a diary of the food consumed and approximate amounts
VACCINATION Subjects will be vaccinated with the standard dose of the Fluzone high dose vaccine from Sanofi Pasteur Inc for each year This vaccine has four times the normal antigen contained in the regular flu vaccine and is specially designed for individuals 60 and older
Criteria for Removal from Study
Subjects will be removed from the study if they do not receive the vaccination Subjects will be removed from study if they have unacceptable toxicity related to the diet
Subjects will be removed from study is they are unable to regain at least 95 of their body weight after the first and 92 after the second cycle Subjects will be removed from study in the presence of a decrease in bioimpedance phase angle exceeding 5 of the baseline value or whenever the phase angle will drop below 5 or alternatively in those patients in which bioimpedance measurements were unreliableunattainable in the presence of a decrease in handgrip strength or in lean body mass detected by DEXA 5 of the baseline value Subjects may voluntarily withdraw from the study at any time for any reason STUDY OBSERVATIONS Visit 1 A complete medical history will be documented at the first visit at the San Martino Hospital Prof
P Odetti MD Prof A Nencioni This will include documentation of chronic diseases and any diseases that could increase risk for influenza including congestive heart failure ischemic heart disease chronic lung disease diabetes kidney failure neoplastic disorders and immune dysfunction weight and performance status All medications will be recorded A physical will be performed and Body Mass Index BMI and body composition will be determined and must be within inclusion parameters Pre-frailty will be diagnosed in participant whether one or two of Fried modified criteria for frailty will be present A blood draw will be performed Baseline laboratory measurements will include a CBC glucose ketone bodies insulin IGF-I IGFBP-1 cytokine panel lymphoidmyeloid ratio CD4CD8 ratio naïve memory T cells ratio and CD8CD28 T cells To assess humoral immunity percentages and absolute numbers of CD19 B cells naïve IgM memory and switch memory B cells will be assessed Briefly PBMCs isolated from whole blood will be enriched for CD19 B cells using anti-CD19 Microbeads Miltenyi Biotech To isolate naïve memory and switch memory cells CD19 cells will be sorted using a flow cytometer after staining with PE-conjugated anti-CD27 biotin-SP-conjugated ChromPure human IgG and 20 μl biotin-SPconjugated ChromPure human IgA To detect CSR in vitro CD19 B cells will be cultured with anti CD40 and IL-4 for 6-7 days AID expression in the stimulated B cells will be measured by RT-PCR E47 expression will be measured by western blot Visit 2 Subjects will return to the clinic upon completion of one cycle of the diet The participants will be subjected to a new medical examination to evaluate their physical activity neuropsychological and to determine the frailty index In addition they will also undergo a body composition assessment by bioimpedance measurement by DEXA scan and by handgrip strength A blood draw will be performed
Laboratory values will include all measurements as above to assess post-diet changes in all the parameters described above Visit 3 two weeks after the second FMD cycle same as in visit 2 In addition all subjects will receive a single injection of influenza vaccination Visit 4 Subjects will return at 4 weeks post vaccination when antibody titers are expected to peak We will perform the clinical examinations and the body composition assessments performed on previous visits on the participants Laboratory measurements will be as above In addition antibody titers in serum will be measured by the haemagglutination inhibition assay Hemagglutinin for each virus strain will be obtained from the CDC stock 2 fold dilutions of serum from 110 to 11024 will be used Chronic agerelated muscle loss affects 30 of individuals over 60 and 50 of individuals over 80 Insufficient protein intake in the elderly may promote loss in muscle mass by preventing muscle protein synthesis Thus bioimpedance measurements and whole body DEXA scans will be conducted in order to ensure that the diet does not cause loss in muscle mass Follow-up The subjects enrolled in the study will be called every three months after the fourth visit see above to undergo physical and psychological examinations in order to evaluate the FMD efficacy in preventing frailty reinforcing the immune system and increasing efficacy of influenza vaccine During the predicted influenza season in the local area subjects will receive weekly phone calls from the trial coordinator to document any symptoms and to remind them to call in to report symptoms If possible NP swabs will be collected within 72 hours of reporting of symptoms by having the RN travel to the subjects homes The incentive for participants to report symptoms early will be access to free diagnosis and referral to the primary physician for treatment of influenza illness Non-compliance will be defined as consumption of 50 of the prescribed diet andor consumption of 150 kcal non-prescribed food on any of the days of the FMD Results for subjects with less than a 50 reduction in IGF-I and 40 reduction in glucose compared to baseline will be analyzed intention-to-treat but a secondary analysis excluding these patients suspected of being non-compliant may be performed
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