List of Clinical Studies

Status: Completed
Participants: FMD in cancer patients; 85 participants
Study: Interventional, Single Group Assignment (February 1, 2017 – March 30, 2019); Estimated Study Completion Date: April 30, 2019
Location: Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
Researcher: Prof. Filippo De Braud (filippo.debraud@istitutotumori.mi.it); Claudio Vernieri, MD, PhD (claudio.vernieri@ifom.eu)

Synopsis: In preclinical studies, cyclic calorie-restricted diets reduce the risk of several cancers and improve the antitumor activity of standard treatments against already established malignancies. In particular, the fasting mimicking diet (FMD), a plant-based, calorie-restricted, low carbohydrate, low-protein diet to be repeated cyclically every 3-4 weeks, enhances the antitumor activity of cytotoxic chemotherapy, while contemporarily protecting healthy tissues and stimulating antitumor immunity. Most of these effects are likely mediated by the reduction of blood glycemia and growth factors, such as insulin and insulin-like growth factor 1 (IGF-1). When administered to healthy volunteers, cyclic FMD has been shown to be safe and capable of reducing risk factors for different chronic diseases. However, the effects of the FMD in cancer patient populations have not been evaluated so far. This study aims to assess the safety, feasibility and metabolic effects of the FMD in cancer patients treated with different standard antitumor therapies. Patients with any malignancy, with the exception of small cell neuroendocrine tumors, will be considered for enrollment in this study. The FMD will be administered up to a maximum of 8 consecutive cycles in combination with standard adjuvant treatments or therapies for advanced disease.

Trial registration: ClinicalTrials.gov -- NCT03340935

Status: Ongoing
Participants: FMD in breast cancer and melanoma; 100 participants
Study: Interventional, Single Group Assignment (July 1, 2018 - May 30, 2020); Estimated Study Completion Date: December 31, 2020
Location: Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
Researcher: Prof. Filippo De Braud (filippo.debraud@istitutotumori.mi.it); Claudio Vernieri, MD, PhD (claudio.vernieri@ifom.eu)

Synopsis: Preclinical evidences suggest that reducing the concentration of blood metabolites and growth factors reduces the in vivo growth of several tumor models, while protecting normal tissues from the cytotoxic effects of chemotherapeutical treatments. In recent years, a plant-based, calorie-restricted, low-carbohydrate, low-protein diet, also known as Fasting Mimicking Diet (FMD), has been proposed as a potential anticancer dietary intervention. The FMD is safe when administered cyclically (every 21-28 days) to healthy volunteers, and is capable of significantly reducing the concentration of plasma glucose, serum insulin and IGF-1, while increasing levels of plasma IGFBPs and ketone bodies. The FMD has been shown to inhibit the in vivo growth of several tumor models, including breast cancer and melanoma mice models. The anticancer effects of the FMD are likely mediated by two concomitant mechanisms: 1) one direct anticancer effect that is mediated by the inhibition of energy production and anabolic pathways, such as protein and fatty acid synthesis, in cancer cells; 2) one indirect effect that is mediated by the activation of antitumor immunity, with the result of enhanced tumor infiltration by cytotoxic CD8+ T-lymphocytes and reduced infiltration by immunosuppressive populations. According to the currently accepted model, the anticancer and immunomodulatory effects of the FMD mostly derive from the reduction of circulating glucose, insulin and IGF-1 levels, and a parallel increase of ketone body and IGF-1 binding protein concentration. However, recent observations in healthy volunteers and cancer patients, suggest that FMD-mediated changes in many other metabolites, such as specific amino acids or fatty acids, could contribute to the cell-autonomous or immune-mediated anticancer effects of the FMD. While the study of the effects of the FMD in combination with standard treatments (e.g. chemotherapy, molecular targeted therapy) in advanced cancers represents the final objective of the ongoing studies, fully uncovering the metabolic and immunological effects of the FMD alone is essential to design future combination studies. From this perspective, the pre- and post-operative clinical settings in cancer patients who are not candidate to other medical treatments represent an ideal context to assess the effects of the FMD without other confounding factors. This trial primarily aims to assess the immunological and metabolic changes induced by the FMD in the pre-operative and post-operative setting in breast cancer and melanoma patients. Three cohorts of patients will be enrolled: 1) Cohort A: patients with resectable breast cancer (cT1N0M0 stage or cT1cN1M0-cT2cN0M0 stages not requiring pre-operative systemic treatment at the judgment of the investigator) who are candidate to curative surgery; 2) Cohort B: patients with malignant melanoma patients candidate to dissection of the lymph node basin because of a positive sentinel lymph node (stage IIIA-IIIB-IIIC); 3) Cohort C: patients with resected malignant melanoma (including radicalization and, in case, lymph node dissection) who are not candidate to any adjuvant treatment, but only to clinical and radiological follow-up (stage IIB-IIC). Patients in cohorts A and B will undergo one 5 days FMD cycle about 13-15 days before surgical removal of primary tumor (breast) or lymph nodes (breast, melanoma). Patients in cohort C will undergo 4 consecutive FMD cycles every 28 days, starting one month after surgery.

Trial registration: ClinicalTrials.gov – NCT03454282

Status: Ongoing
Participants: Chemolieve in breast and prostate cancer; 120 participants (90 patients for breast cancer and 30 patients for prostate cancer)
Study: Randomized, Interventional, Parallel Assignment (January 29, 2013 – January 29, 2020); Estimated Study Completion Date: January 29, 2021
Location: University of Southern California, Los Angeles, CA; in collaboration with Norris Cancer Center and LAC+USC
Researcher: Dr. David Quinn (diquinn@med.usc.edu); Dr. Irene Kang (Irene.Kang@med.usc.edu); Mahshid Shelechi, MS RD (shelehch@usc.edu)

Synopsis: We are studying the effects of a medically designed low-calorie diet for women with breast cancer and men with prostate cancer receiving chemotherapy. We believe the diet will help prevent or lessen chemotherapy side effects such as nausea and fatigue and may also help chemotherapy be more effective against the cancer. We want to obtain preliminary estimates of the impact of a restricted diet on toxicity and efficacy of chemotherapy for breast and prostate cancer

This randomized phase II trial studies how well a controlled low-calorie diet works in reducing side effects and increasing response to chemotherapy in patients with breast or prostate cancer. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Eating a special diet with low calories may reduce the side effects of chemotherapy and improve the response to treatment.

Trial registration: ClinicalTrials.gov – NCT01802346

Status: Ongoing
Participants: ProLon and solid/hematologic malignancies; 60 patients
Study: Phase II Clinical Study (Start Date: November 22, 2017 – April 15, 2020); Estimated Study Completion Date: September 14, 2020
Location: University of Genova, Genova, Italy
Researcher: Prof. Alessio Nencioni, MD, PhD (alessio.nencioni@unige.it); Francesca Valdemarin (francescavaldemarin@me.com)

Synopsis: Every year in Europe, around 3.5 million new cases of cancer are diagnosed and 1.8 million patients die of cancer. This scenario generates the need to evaluate new therapeutic approaches, including metabolic approaches and approaches that exploit new, emerging properties of the neoplastic cells themselves. Numerous studies show how fasting cycles exert powerful antitumor effects in experimental animals, where these effects are reported by laboratories independent both in models of solid tumors (such as breast cancer, and lung cancer) of the colorectal, melanomas and gliomas that of hematological tumors (especially of leukemia acute lymphatic system). Moreover, in animal models, fasting cycles have been shown to increase both the tolerability and the efficacy of chemotherapeutic agents, including cyclophosphamide, etoposide, doxorubicin, oxaliplatin and cisplatin. Specifically, in the case of doxorubicin, fasting has been shown to exert protective effects also in case of cardiac toxicity, while in the case of cisplatin, fasting has been shown to reduce neurological side effects. At least in part, the antineoplastic action and the strengthening of chemotherapy by fasting appears to be due to the promotion of antitumor immunity and sensitization of neoplastic cells to the action of the immune system. These observations led to the development of fasting-mimicking diets (FMD) which, on the basis of surveys, are better accepted than fasting by patients and that recreate the antineoplastic and protective effects and protect from the side effects of fasting itself.

Trial registration: ClinicalTrials.gov – NCT03595540

Status: Ongoing
Participants: ProLon and risk of breast cancer (300 patients)
Study: Randomized Pilot Study (June 1, 2018 - May 31, 2019); Estimated Study Completion Date: May 31, 2020
Location: University Hospital, Policlinico Paolo Giaccone di Palermo, Palermo, Italy
Researcher: Prof. Mario Mirisola (mario.mirisola@unipa.it); Prof. Antonio Russo, +091 6552500

Synopsis: Women carrying harmful mutation in BRCA1 or BRCA2 gene are at higher risk to develop breast and/or ovarian cancer than the general population. Many observations lead to the hypothesis that breast cancer risk may be increased in women with elevated plasma insulin-like growth factor 1 (IGF-1) and insulin levels. Targeting the IGF system is therefore a promising anticancer therapy and a new tool for oncologists. Evidence from bio-gerontology research from our laboratories show that cycles of short-term fasting/starvation (STS) or low-calorie diet can improve health span of laboratory animals, whose effect is partly mediated by reduced circulating IGF-1. Investigators in our group have demonstrated that protein consumption, especially animal proteins, increases IGF-1 level and is associated with elevated cancer risk in a US cohort ranging from age 50 to 65 (PMID: 26094889). It was also showed that alternating prolonged fasting and nutrient-rich medium extended yeast lifespan independently of the status of the established pro-longevity genes. Prolonged Fasting (PF) has also been shown in preliminary studies to decrease the side effects of chemotherapy, an effect now being tested in multiple larger randomized clinical trials (PMID: 26590477). The main hypothesis of this proposal is that a combination of protein restriction, fasting, fasting mimicking diet (FMD), and restriction of specific amino acids may be able to decrease cancer incidence in a cohort of people at high risk of developing tumors (BRCA1/2). Our group plan to verify the safety, effectiveness and impact of a specially formulated longevity dietary regimen (low protein fish- and plant-based) and of FMD repeated cycles on the levels of endogenous hormones in a cohort of people at increased cancer risk. Since the duration of the project will not give us the opportunity to directly measure cancer incidence in humans we will test: 1a) the variation of a number of widely recognized susceptibility biomarkers predictive of cancer incidence in a cohort human carriers of BRCA1/2 mutations in response to the dietary interventions; 1b) cancer incidence and progression in genetically engineered mice (K14Cre Brca1flox/flox Trp53+/flox and K14Cre Brca1+/flox Trp53-/- mice) predisposed to develop hereditary breast cancer in response to corresponding dietary interventions. Investigators will also test epigenetic alterations associated with these interventions in: 2a) DNA samples from muscle biopsies of a subgroup of humans; 2b) breast epithelial tissue in mice.

Trial registration: ClinicalTrials.gov – NCT03570125

Status: Completed
Participants: FMD and Breast Cancer; 131 participants
Study: Randomized, Interventional, Parallel Assignment (February 2014 – November 2018)
Location: Leiden University Medical Center, Leiden, Netherlands
Researcher: Judith R Kroep, MD, PhD +31715263464 (j.r.kroep@lumc.nl); Stefanie de Groot, MD +31715263464 (s.de_groot2@lumc.nl); Hanno Pijl, MD, PhD (H.Pijl@lumc.nl); Koos JM van der Hoeven, MD, PhD;

Synopsis: Preclinical studies provide strong support for the concept that fasting evokes resistance to multiple forms of stress. Fasting reduces plasma levels of growth factors and modulates intracellular nutrient sensing systems, thereby diverting energy from growth to maintenance. Accordingly, the currently available preclinical evidence suggests that short-term fasting protects normal cells against the perils of chemotherapy. In contrast, cancer cells are not protected, as a result of their self-sufficiency in growth signals. This phenomenon is termed Differential Stress Resistance (DSR). DSR reduces the severity of toxic side-effects of chemotherapy and interestingly, it simultaneously renders cancer cells more vulnerable to chemotherapeutics. Importantly, extensive preclinical evidence and preliminary clinical data indicate that a specifically designed very low calorie, low amino acid substitution diet (“Fasting Mimicking Diet, FMD”) has effects on cancer therapy that are very similar to those of fasting. This study aims to evaluate the impact of the FMD on tolerance to and efficacy of neoadjuvant chemotherapy in women with stage II or III breast cancer.

Trial registration: ClinicalTrials.gov – NCT02126449

Status: Ongoing
Participants: Fasting and advanced metastatic prostate cancer; 60 participants
Study: Randomized, Interventional, Parallel Assignment (April 2016 – July 2019); Estimated Study Completion Date: December 2019
Location: Charite University, Berlin, Germany
Researcher: Dr. Ursula Steiner +49 30 8445 2577 (ursula.steiner@charite.de); Dr. Kurt Miller +49 30 8445 2577 (kurt.miller@charite.de)

Synopsis: Prostate cancer is in Germany with approximately 25% of all cancers the most common cancer among man. Assumably there will be an increase in prostate cancer in the next few years because of demographic factors. The progressive metastatic prostate cancer often develops an androgen resistance. This so-called Castration-Resistant Prostate Cancer (CRPC) is not responsive to androgen deprivation therapy. Depending on symptoms and progression first-line chemotherapy – docetaxel and abiraterone are available.

Intermittent fasting as a form of caloric restriction has been studied most extensively experimentally in recent years. It showed consistent beneficial effects on relevant inflammatory and oncological pathways. In the field of preclinical oncology research groups have recently focused on intermittent fasting with chemotherapeutic treatment and promising experimental data have been published. In summary, the combination of fasting and chemotherapy was more effective in various cancer animal models than chemotherapy alone.

Trial registration: ClinicalTrials.gov – NCT02710721

Status: Completed
Participants: Fasting and chemotherapy; 10 patients
Study: Case Report
Location: University of Southern California, Los Angeles, CA
Researcher: Fernando M. Safdie; Valter Longo, PhD

Published: Safdie, F. M., Dorff, T., Quinn, D., Fontana, L., Wei, M., Lee, C., … Longo, V. D. (2009). Fasting and cancer treatment in humans: A case series report. Aging (Albany NY), 1(12), 988–1007.

Abstract: Short‐term fasting (48 hours) was shown to be effective in protecting normal cells and mice but not cancer cells against high dose chemotherapy, termed Differential Stress Resistance (DSR), but the feasibility and effect of fasting in cancer patients undergoing chemotherapy is unknown. Here we describe 10 cases in which patients diagnosed with a variety of malignancies had voluntarily fasted prior to (48‐140 hours) and/or following (5‐56 hours) chemotherapy. None of these patients, who received an average of 4 cycles of various chemotherapy drugs in combination with fasting, reported significant side effects caused by the fasting itself other than hunger and lightheadedness. Chemotherapy associated toxicity was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) of the National Cancer Institute (NCI). The six patients who underwent chemotherapy with or without fasting reported a reduction in fatigue, weakness, and gastrointestinal side effects while fasting. In those patients whose cancer progression could be assessed, fasting did not prevent the chemotherapy‐induced reduction of tumor volume or tumor markers. Although the 10 cases presented here suggest that fasting in combination with chemotherapy is feasible, safe, and has the potential to ameliorate side effects caused by chemotherapies, they are not meant to establish practice guidelines for patients undergoing chemotherapy. Only controlled‐randomized clinical trials will determine the effect of fasting on clinical outcomes including quality of life and therapeutic index.

Status: Completed
Participants: Fasting and Chemotherapy in HER2- negative breast cancer; 13 patients
Study: Randomized Pilot Study, Interventional, Parallel Assignment (March 2011 – April 2013); Estimated Study Completion Date: January 2015
Location: Leiden University Medical Center, Leiden, Netherlands
Researcher: Judith R Kroep, MD, PhD +31 71 5263464 (j.r.kroep@lumc.nl); Stefanie de Groot, MD
+31 71 5263464 (s.de_groot2@lumc.nl)

Published: De Groot, S., Vreeswijk, M. P., Welters, M. J., Gravesteijn, G., Boei, J. J., Jochems, A., … Kroep, J. R. (2015). The effects of short-term fasting on tolerance to (neo) adjuvant chemotherapy in HER2-negative breast cancer patients: a randomized pilot study. BMC Cancer, 15, 652.

Synopsis: Preclinical evidence shows that short-term fasting (STF) protects healthy cells against side effects of chemotherapy and makes cancer cells more vulnerable to it. This pilot study examines the feasibility of STF and its effects on tolerance of chemotherapy in a homogeneous patient group with early breast cancer (BC).

Methods: Eligible patients had HER2-negative, stage II/III BC. Women receiving (neo)-adjuvant TAC (docetaxel/doxorubicin/cyclophosphamide) were randomized to fast 24 h before and after commencing chemotherapy, or to eat according to the guidelines for healthy nutrition. Toxicity in the two groups was compared. Chemotherapy-induced DNA damage in peripheral blood mononuclear cells (PBMCs) was quantified by the level of γ-H2AX analyzed by flow cytometry.

Results: Thirteen patients were included of whom seven were randomized to the STF arm. STF was well tolerated. Mean erythrocyte- and thrombocyte counts 7 days post-chemotherapy were significantly higher (P = 0.007, 95 % CI 0.106-0.638 and P = 0.00007, 95 % CI 38.7-104, respectively) in the STF group compared to the non-STF group. Non-hematological toxicity did not differ between the groups. Levels of γ-H2AX were significantly increased 30 min post-chemotherapy in CD45 + CD3- cells in non-STF, but not in STF patients.

Conclusions: STF during chemotherapy was well tolerated and reduced hematological toxicity of TAC in HER2-negative BC patients. Moreover, STF may reduce a transient increase in, and/or induce a faster recovery of DNA damage in PBMCs after chemotherapy. Larger studies, investigating a longer fasting period, are required to generate more insight into the possible benefits of STF during chemotherapy.

Trial registration: ClinicalTrials.gov -- NCT01304251

Status: Ongoing
Participants: Fasting before chemotherapy; 70 patients [Published Data on 20 patients]
Study: Randomized, Interventional, Parallel Assignment (July 9, 2009 – July 9, 2021)
Location: University of Southern California, Los Angeles, CA; in collaboration with Norris Cancer Center
Researcher: Valter Longo, PhD; Dr. David Quinn (diquinn@med.usc.edu); Shahmim Jhimlee (jhimlee_s@med.usc.edu)

Published: Dorff, T. B., Groshen, S., Garcia, A., Shah, M., Tsao-Wei, D., Pham, H., … Quinn, D. I. (2016). Safety and feasibility of fasting in combination with platinum-based chemotherapy. BMC Cancer, 16, 360.

Synopsis: This partially randomized clinical trial studies short-term fasting in reducing side effects in patients receiving gemcitabine hydrochloride and cisplatin for advanced solid tumors. Short-term fasting before chemotherapy may reduce the side effects caused by chemotherapy. Drugs used in chemotherapy, such as gemcitabine hydrochloride and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing.

Objectives:

To determine the safety and feasibility of short-term fasting prior to administration of combination chemotherapy with platinum in patients with advanced solid tumor malignancies.

1. To evaluate the toxicity profile of platinum-based chemotherapy in subjects who eat normally compared to those who undertake short-term starvation.

III. To investigate changes in plasma insulin, glucose, IGF1 and IGF binding protein (IGFBP) levels, and oxidative stress markers in subjects who undertake short-term fasting compared to controls.

1. To investigate whether changes in grp78 expression occur after fasting and after chemotherapy administration in human subjects.

Short-term starvation prior to chemotherapy administration protects mice against toxicity. We undertook dose-escalation of fasting prior to platinum-based chemotherapy to determine safety and feasibility in cancer patients.

Methods: 3 cohorts fasted before chemotherapy for 24, 48 and 72 h (divided as 48 pre-chemo and 24 post-chemo) and recorded all calories consumed. Feasibility was defined as ≥ 3/6 subjects in each cohort consuming ≤ 200 kcal per 24 h during the fast period without excess toxicity. Oxidative stress was evaluated in leukocytes using the COMET assay. Insulin, glucose, ketones, insulin-like growth factor-1 (IGF-1) and IGF binding proteins (IGFBPs) were measured as biomarkers of the fasting state.

Results: The median age of our 20 subjects was 61, and 85 % were women. Feasibility criteria were met. Fasting-related toxicities were limited to ≤ grade 2, most commonly fatigue, headache, and dizziness. The COMET assay indicated reduced DNA damage in leukocytes from subjects who fasted for ≥48 h (p = 0.08). There was a non-significant trend toward less grade 3 or 4 neutropenia in the 48 and 72 h cohorts compared to 24 h cohort (p = 0.17). IGF-1 levels decreased by 30, 33 and 8 % in the 24, 48 and 72 h fasting cohorts respectively after the first fasting period.

Conclusion: Fasting for 72 h around chemotherapy administration is safe and feasible for cancer patients. Biomarkers such as IGF-1 may facilitate assessment of differences in chemotherapy toxicity in subgroups achieving the physiologic fasting state. An ongoing randomized trial is studying the effect of 72 h of fasting.

Trial registration: ClinicalTrials.gov -- NCT00936364

Status: Completed
Participants: FMD and gynecological cancer; 50 participants
Study: Randomized, Interventional, Crossover Assignment (October 2013 – March 2015)
Location: Charite University, Berlin, Germany
Researcher: Andreas Michalsen, MD, PhD (andreas.michalsen@immanuelalbertinen.de)

Published: Bauersfeld SP, Kessler CS, Wischnewsky M, Jaensch A, Steckhan N, Stange R, Kunz B, Brückner B, Sehouli J, Michalsen A. The effects of short-term fasting on quality of life and tolerance to chemotherapy in patients with breast and ovarian cancer: a randomized cross-over pilot study. BMC Cancer. 2018 Apr 27;18(1):476. doi: 10.1186/s12885-018-4353-2.

Synopsis: This pilot trial aimed to study the feasibility and effects on quality of life (QOL) and well-being of short-term fasting (STF) during chemotherapy in patients with gynecological cancer.

Methods: In an individually randomized cross-over trial patients with gynecological cancer, 4 to 6 planned chemotherapy cycles were included. Thirty-four patients were randomized to STF in the first half of chemotherapies followed by normocaloric diet (group A; n = 18) or vice versa (group B; n = 16). Fasting started 36 h before and ended 24 h after chemotherapy (60 h-fasting period). QOL was assessed by the FACIT-measurement system.

Results: The chemotherapy-induced reduction of QOL was less than the Minimally Important Difference (MID; FACT-G = 5) with STF but greater than the MID for non-fasted periods. The mean chemotherapy-induced deterioration of total FACIT-F was 10.4 ± 5.3 for fasted and 27.0 ± 6.3 for non-fasted cycles in group A and 14.1 ± 5.6 for non-fasted and 11.0 ± 5.6 for fasted cycles in group B. There were no serious adverse effects.

Conclusion: STF during chemotherapy is well tolerated and appears to improve QOL and fatigue during chemotherapy. Larger studies should prove the effect of STF as an adjunct to chemotherapy.

Trial registration: ClinicalTrials.gov – NCT01954836

Status: Planned
Participants: FMD and Lung cancer; 40 patients
Study: Randomized Clinical Trial (Anticipated Start Date: April 15, 2020)
Location: Eskenazi Hospital and Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN
Researcher: Shadia Jalal, MD (sjalal@iu.edu); Maggie Uhrich, RN (muhrich@iu.edu)

Synopsis: Cancer cells use an increased supply of glucose to make energy and do not have protection against fasting that normal cells do. Because of this, researchers would like to study how fasting may help chemotherapy target cancer cells instead of normal cells. Initial studies suggest that fasting may decrease the side effects of chemotherapy and increase the chances of your cancer responding to the chemotherapy. Patient populations will have non-small cell lung cancer in which chemo-immunotherapy with carboplatin/pemetrexed and pembrolizumab have been recommended to treat the cancer as part of standard care.

Primary Objectives - To determine the effect of Fasting-mimicking diet (FMD) on circulating tumor cells (CTCs) in patients with advanced NSCLC receiving chemo-immunotherapy.

To compare an absolute reduction and/or a percentage reduction in CTCs in patients receiving FMD compared to regular diet (RD)

To assess DNA damage via measurement of γ-Η2ΑΧfoci in CTCs compared to PBMCs of patients receiving FMD or RD

Secondary Objectives – To determine the clinical efficacy of FMD compared to RD by comparing the response rate (RR) and progression-free survival (PFS)

To demonstrate the safety profile of FMD in conjunction with chemo-immunotherapy

Correlative Objectives - To demonstrate an increase in platinum lesions measured by ICP Mass spectrometry in tumor tissue (when available) and PBMCs of patients receiving FMD compared to RD

To demonstrate increase in Tumor-infiltrating lymphocytes in patients undergoing FMD compared to RD by obtaining optional tumor tissue samples when available.

To determine effect of FMD on immune regulation compared to RD

To demonstrate change in FDG avidity in patients receiving FMD compared to RD when optional post-treatment PET scans are available

To determine compliance to FMD

To determine effect of FMD on QoL compared to RD

Trial registration: ClinicalTrials.gov – NCT03700437

Status: Completed
Participants: ProLon and muscular fatigue and strength; 72 participants
Study: Randomized Clinical Trial (April 12, 2017 – June 06, 2020); Actual Start Date: October 16, 2017; Study Stop Date: January 2020
Location: University of Verona, Verona, Italy
Researcher: Prof. Matteo Bertucco (matteo.bertucco@univr.it)

Synopsis: The aim of the study is to test a Fasting Mimicking Diet for its efficacy on improving muscular resistance and endurance. Intermittent or Periodic Fasting have been reported to promote lifespan extension and provide a range of protective effects, including hematopoietic stem cell generation and protection against chemotherapy-induced immunosuppression. However, it is still unknown whether stem cell generation due to intermittent or Periodic Fasting has effects on muscular resistance and endurance. We will perform a randomized clinical trial to test the efficacy of the FMD on improving muscular strength, muscular resistance and endurance in physically active young adults (18-40 years of age). The study will include two arms: Control (Placebo diet) and FMD (3 cycles of 5 days fasting-mimicking diet within two months). Study endpoints will include muscular strength evaluation of lower limbs, cardio-pulmonary responses, neuromuscular function and muscle architecture.

Status: Ongoing
Participants: Prolon and glomerulonephritis and chronic kidney disease; 32 patients
Study: Prospective Clinical Trial, Crossover Assignment (April 2018 - Jan 2020)
Location: Sapienza University, Rome, Italy
Researcher: Prof. Alessandro Laviano, MD, PhD (alessandro.laviano@uniroma1.it)

Synopsis:

Primary endpoints:

1.Evaluate the reduction of IGF-1 after three cycles of FMD in patients affected by primary glomerulonephritis with MRC (3 stage KDOQI).

Secondary endpoints:

2.To evaluate the systemic effects of the use of FMD through some markers of inflammation, oxidative stress and endothelial dysfunction, major cardiovascular risk factors, in patients with MRC (3 stage KDOQI).

3.Evaluate the systemic effects of the use of FMD on the cognitive component.

4.Evaluate the systemic effects of the use of FMD on regenerative capacity, leading to a possible increase in renal stem cells CD133 +, CD24 +, CD45 +, CD34 + and CD309 + in blood and urine.

Status: Ongoing
Participants: ProLon + Supplement AD (Alzheimer’s Disease) and AD or MCI (Mild Cognitive Impairment); 60 patients affected by mild AD (MMSE 18-23) and 60 patients affected by MCI
Study: Phase I/II Randomized Clinical Trial (October 8, 2019 – December 31, 2021)
Location: University of Genova, Genova, Italy

Synopsis: In experimental animal models, caloric restriction diets have shown protective effects on the aging process, on oxidative stress and on the process of neurodegeneration, factors implicated in the pathogenesis of Alzheimer’s disease. Diet cycles with low levels of sugars and proteins followed by diets with normal levels of these lead to temporary reductions in growth hormone levels and IGF-1. Both are potential mediators of the neuroprotective and regenerative effects of these diets not only in mice, but also in monkeys and men. However, strongly calorie restricted diets are often difficult to maintain over time and are frequently associated with even significant side effects and with progressive weight loss, particularly of lean mass. In a mouse model of AD, it has been shown that periodic cycles of a “fasting-mimicking” diet (FMD) restricted in protein content (protein-restricted – PR-FMD) but not in terms of calories are able to reduce levels circulating plasma IGF-1 with significant effects of contrast to the process of neurodegeneration. In particular, such FMD has been shown to reduce by about 30-70%, the levels of hyperphosphorylated tau protein (one of the typical markers of AD) at the hippocampal level, reducing the correlated age deficit of cognitive performance. More recently, a significant neuro-regenerative effect (associated with a clinical improvement of motor coordination and memory) has been demonstrated in mice subjected to a diet based on a similar FMD during their “average life” (months 16-30).

Recent clinical studies have shown that FMDs are generally safe and well tolerated in healthy subjects and in people with multiple sclerosis, even with multiple monthly cycles and in individuals over 65. Furthermore, it is important to underline that, in healthy subjects, cycles of FMD have reduced various risk factors for aging diseases (including AD), including arterial hypertension, pre-diabetes, accumulation of visceral adipose tissue and high circulating levels of IGF-1 and C-reactive protein. Recently, in a study conducted at the University of Southern California (USC), 3 cycles of a week-long PR-FMD have led to a significant improvement in cognitive performance in healthy volunteers.

Status: Ongoing
Participants: ProLon and Multiple Sclerosis; 20 patients
Study: Monocenter, Open Label, Single-Arm, Not Controlled Run-In Study; (Start Date: Dec 16, 2019); Estimated Study Stop Date: Dec 2020
Location: Clinica Neurologica, Ospedale Policlinico S. Martino, Genova, Italy
Researcher: Prof. Gianluigi Mancardi (glmancardi@neurologia.unige.it)

Synopsis:  

Primary objective:

To evaluate the safety and tolerability of 3 cycles of a 7 day Fasting Mimicking Diet (FMD) as a potential support to the management of patients affected by RRMS, already treated with interferon-beta-1a (22 or 44 µgx3).

Secondary objectives:

- To assess the patients’ compliance to the FMD;

- To determine if a FMD has an effect on general health status, disability, fatigue, depression and cognitive functions;

- To evaluate if a FMD has some effect on the neurological clinical status of the patient;

- To evaluate if a FMD has some influence on the inflammatory activity of the disease as evaluated by Magnetic Resonance Imaging (MRI);

- To quantify the consequences of a FMD on nutritional status and body composition;

- To evaluate the changes in the composition and function of the gut microbiota and in the peripheral composition of the immune response;

- To assess if a FMD has some effect in preventing neurodegeneration.

Status: Completed
Participants: 20 participants
Study: Randomized, Interventional, Parallel Assignment (September 12, 2018 – May 23, 2019); Estimated Study Completion Date: June 27, 2019
Location: Azienda Ospedaliera Universitaria Policlinico Paolo Giaccone Palermo
Researcher: Giuseppe Maniaci, MD

Synopsis: Depression has to be considered as a systematic illness involving the whole body, it is often associated with low-grade inflammation and alterations of the microbiome. In this regard, an unhealthy diet increases the risk of the onset of this disorder, therefore an integrated treatment including a healthy diet could be more effective. The aim of our study was to verify the efficacy of a structured FT program, delivered in individual setting, for patients with depression (PSY group), and to verify whether the association of a FMD protocol with the structured FT program significantly improves clinical outcomes (PSY-FMD group). After a psychiatric, psychological and anthropometric assessment, depressed patients were randomly assigned to psychotherapy and diet (PSY-FMD) or just psychotherapy (PSY). PSY-FMD participants received 20 individual sessions of Functional Psychotherapy. Each session attended twice a week for the first 8 weeks and once a week for the remaining 4. Furthermore, they received a nutritional consultation and prescription of a Fasting Mimicking Diet. PSY group received just the psychotherapy protocol and the nutritional consultation. All patients were retested at the end of the treatment and at follow-up 3 months after the last session. In both groups was highlighted a strong effectiveness of treatments on depression, self-esteem and quality of life. In the PSY-FMD group compared to PSY a significant effect was found on the improvement of self-esteem and quality of life. Furthermore, a significant reduction of BMI was found in the PSY-FMD group. The current study supports the effectiveness of the combination of psychotherapy with a fasting mimicking diet in adult depressed patients.

Trial registration: ClinicalTrials.gov -- NCT04050475

Status: Completed
Participants: FMD and CVD and CHD risk factors; 80 subjects (40 subjects in the control group and 40 subjects in the treatment group); 35-75 years old
Study: Randomized Clinical Trial (March 1, 2019 – November 22, 2019); Estimated Study Completion Date: January 31, 2020
Location: Hypertension Institute (HI) of Nashville, Nashville, TN and University of Southern California (USC), Los Angeles, CA
Researcher: Mark C. Houston, MD, MS, MSc (boohouston@comcast.net); Sissy Denton, RN, BSN (sissy.denton@comcast.net)

Synopsis: Determine the effects of the Fasting Mimicking Diet (FMD) on cardiovascular biomarkers, Coronary Heart Disease (CHD) risk factors (body weight, BMI, body composition, blood pressure, serum lipid levels and dysglycemia blood measurements), non-invasive cardiovascular testing for endothelial function, arterial stiffness of large and small arteries, and autonomic function testing in adult subjects over a five-month study period.

The ProLon arm participants are consuming the diet once a month for 4 months, then returning after three months for follow-up. The Mediterranean arm participants are following guidelines given regarding Mediterranean eating, same time frame as above.

Trial registration: ClinicalTrials.gov -- NCT04150159

Status: Ongoing
Participants: Chemolieve in prostate cancer patients at risk of metabolic syndrome (10-15 patients, 18-80 years old)
Study: Prospective Clinical Study (Start Date: January 2019; Estimated End Date: June 2020)
Location: Prostate Cancer Institute, Galway Clinic and National University of Galway (NUIG), Ireland
Researcher: Prof. Frank Sullivan, MBBS, MSc (frank.sullivan@galwayclinic.com); Valter Longo, PhD

Synopsis: We aim to validate an approach to measuring, tracking and addressing Oxidative Stress and Inflammation status as key indicators of physiological adaptation, fatigue and disease states in cancer patients, and ultimately improve recovery in patients with Cancer Related Fatigue (CRF) in maladapted and fatigued states. We further wish to monitor the role of supportive recommendations (e.g. hydration, diet, rest, exercise, stress reduction) often recommended for these symptoms. This will be done by describing and quantitating baseline patient efforts as best as possible, in this broad cohort. Where possible evidence-based suggestions and advice will be given to patients, to help them with their diet, exercise and stress management. It is recognized that this study will NOT lead us to recommendations as to the value of any intervention observed, it will merely serve as a baseline, from which potential further studies might lead to recommendations in the future.

Trial registration: ClinicalTrials.gov -- NCT04292041

Status: Planned
Participants: 20 patients with GBM enrolled after tumor resection and prior to chemoradiotherapy. Enrolled subjects will be placed on 12 weeks trial of the dietary intervention while receiving standard of care cancer treatment (Radiation + Temozolomide)
Study: Prospective, Single-Arm Pilot Study; [Anticipated Start Date: May 2020]
Location: Virginia Tech Carillon School of Medicine, Roanoke, Virginia
Researcher: Dr. Lisa Apfel; Steven Svoboda (sasvoboda@carilionclinic.org)

Synopsis: There is an increasing interest in the use of the ketogenic diet as an adjuvant therapy for glioblastoma multiforme (GBM) patients due to the substantial amount of preclinical and clinical literature demonstrating anti-neoplastic efficacy and safety. The ketogenic diet is postulated to work by simulating the metabolic response to fasting by promoting the utilization of ketones as a primary energy source, and depriving the glycolytic pathways utilized by malignant glioma cells for growth. Current ongoing clinical trials are investigating the most promising ketogenic regimen for glioblastoma patients, as well as, compatibility with other anti-cancer treatments, feasibility, safety, and impact on quality of life.

Objectives: The primary aim of this pilot intervention study is to obtain preliminary evidence of the feasibility and tolerability of a novel ketogenic diet protocol in newly diagnosed GBM patients. Secondary aims include evaluating safety, efficacy, and patient impact of the diet. The monthly protocol consists of a patented 5 days fasting mimicking diet program (L-Nutra, CA, USA) followed by a modified ketogenic diet and time restricted feeding.

Methods: A prospective, single-arm pilot study will be undertaken in 20 subjects with GBM. Patients will be enrolled after tumor resection and prior to chemoradiotherapy. Enrolled subjects will be placed on a 12-week trial of the dietary intervention while receiving standard of care cancer treatment (Radiation + Temozolomide). A study dietitian will provide guidance and teaching of the diet protocol, as well as, monitoring and diet adjustment to ensure adherence. Feasibility will be assessed by enrollment and retention rates, dietary adherence and tolerability questionnaires, and weekly blood ketone checks. Patient impact will be assessed by quality of life and cognitive function questionnaires, anthropometric and biochemical changes, and reported adverse effects.

Expected Outcomes: The results of this pilot study will be used to inform the feasibility and methodological design of future clinical trials investigating the effectiveness of this nutritional protocol as an adjuvant metabolic therapy in the management of patients with GBM.

Status: Ongoing
Participants: 90 South Asian type 2 diabetic patients with micro-albuminuria receiving a food supplement, placebo capsule or the 5 days fasting mimicking diet Prolon
Study: Double-Blind, Randomized, Controlled, Interventional, Parallel Assignment (May 3, 2018 - December 31, 2019)
Location: Leiden University Medical Centre, Leiden, Netherlands
Researcher: Anouk I. M. van der Velden, MD (a.i.m.van_der_velden@lumc.nl); Daphne H.T. ljpelaar, MD, PhD (D.H.T.ljpelaar@lumc.nl); Ton J. Rabelink, MD, PhD (A.J.Rabelink@lumc.nl)

Synopsis: Micro- and macrovascular complications are the pathological hallmarks of diabetes mellitus, with diabetic nephropathy as one of the most serious microvascular complications. South Asians have a high incidence of type 2 diabetes and a higher change to progress to end-stage renal disease than West European patients, which may be due to a higher sustained systemic and glomerular inflammation.

The endothelial glycocalyx, covering endothelial cells, is essential for maintaining vascular homeostasis. In the diabetic environment, impairment of the glycocalyx can be induced by invading macrophages which excrete the glycocalyx degrading enzyme heparanase and its activator cathepsin L. In the glomerulus, impairment of the glycocalyx results in increased permeability for albumin alongside renal and vascular inflammation. SDF-imaging is a non-invasive technique to visualize the sublingual endothelial glycocalyx and obtains parameters that reflect the microvascular health, combined in the Microvascular Health Index (MHI). In the present study, we investigate if dietary interventions, a food supplement which provides the nutritional building blocks to support and maintain the endothelial glycocalyx or a 5 days fasting mimicking diet to reduce the overall inflammatory burden, can aid in restoration of the endothelial glycocalyx and in turn improve the microvascular health within 3 months.

Trial registration: ClinicalTrials.gov -- NCT03889236

Status: Ongoing
Participants: Patients with diabetes mellitus type 2 and diabetic nephropathy; 60 participants
Study: Randomized, Controlled Clinical Trial (Start Date: March 2018, Stop Date: March 2020)
Location: Department of Endocrinology and Clinical Chemistry (Internal Medicine I), University Hospital Heidelberg, Heidelberg, Germany
Researcher: Alba Sulaj, MD (Alba.Sulaj@med.uni-heidelberg.de)

Synopsis: Fasting has been shown to cause beneficial effects on lifespan, stress-resistance and against oxidative damage. To minimize the burden of fasting, a “fasting-mimicking-diet” (FMD) was developed. FMD mimics metabolically fasting effects in the organism through a low calorie, low protein, low carbohydrate and high in unsaturated fats dietary composition. The aim of this study is to investigate the late complications of diabetes during periodic FMD intake in patients with diabetes mellitus type 2 and diabetic nephropathy. This is a prospective randomized controlled monocentric intervention study. Patients with diabetes mellitus type 2 and elevated albuminuria are randomized in two groups: an intervention group where patients receive periodically for 5 consecutive days once a month FMD, and a control group where patients receive Mediterranean diet. Study duration is 6 months. Both groups undergo regular examinations regarding the late complications of diabetes. Change of albuminuria is analyzed as primary endpoint.

Trial Registration: German Register for Clinical Studies (DRKS) -- DRKS00014287

Status: Planned
Participants: 60 women treated with adjuvant AI + 5 days Chemolieve for 12 weeks (1cycle/month to 3 cycles)
Study: Prospective, Randomized Clinical Trial [Estimated Start Date: May-Jun 2020]
Location: Instituto Europeo di Oncologia, Milano, Italy
Researcher: Ida Minchella, MD (ida.minchella@ieo.it); Giuseppe Curigliano, MD, PhD (giuseppe.curigliano@ieo.it); Valter Longo, PhD

Synopsis: In postmenopausal women with hormone receptor-positive early-stage breast cancer, the use of aromatase inhibitors (AIs) is associated with improved clinical outcomes compared with tamoxifen therapy. Adjuvant endocrine therapy is not associated with the more severe, acute toxicities of chemotherapy, and can therefore be taken for many years. At present, the standard duration of postoperative adjuvant endocrine therapy is 5-10 years. Women receiving such endocrine therapy may experience treatment-related side effects that negatively affect health-related quality of life (QoL) and adherence to therapy. Prevention and treatment of adverse events associated with long-term endocrine therapy is particularly important in the adjuvant setting, where patients are clinically cancer free. There have been lots of controversies on the effect of AIs to lipid profile or CVD (cardiovascular disease) risk. The proposed prospective randomized clinical trial will test the hypothesis that FMD as an adjuvant intervention will reduce total cholesterol levels by AIs adjuvant treatment in post-menopausal women with early breast cancer. This study will enter a total of 60 women (>18 years old) with a histologic diagnosis of endocrine responsive early breast cancer. Following primary surgical therapy, all patients will receive defined standard systemic therapy. Patient on AIs treatment (at least 1 year of treatment) will be randomized to 12 weeks of FMD or only to a control group (non-intervention group, NIG).

Status: Ongoing
Participants: 20 male and female subjects between 18 and 70 years of age, diagnosed with inflammatory cardiomyopathy; Total of 40 patients (20 treated and 20 placebo)
Study: Phase I Pilot Study, Randomized, Placebo-Controlled (Start Date: August 8, 2019, Estimated Stop Date: August, 2021)
Location: Campus Benjamin Franklin, Charité Universitätsmedizin Berlin, Germany
Researcher: Dr. Bettina Heidecker (bettina.heidecker@charite.de)

Synopsis: This study is meant to evaluate whether ProMet, a dietary intervention mimicking fasting for five days per month, can reduce inflammatory cytokines Th1 and Th17 and increase T regulatory cells and naïve T cells compared to placebo group in patients with inflammatory cardiomyopathy. Patients will undergo 6 cycles of diet (ProMet or regular diet) and a 1 year follow up, and will be assessed for the composition of the immune cells in the peripheral blood, blood cytokines, functional parameters (left ventricular ejection fraction, arrhythmias, performance during exercise stress testing), and quality of life.

Primary Objective:

To evaluate whether a periodic fasting-mimicking diet affects the composition of immune cells in the peripheral blood of patients with inflammatory cardiomyopathy based on myocardial biopsy

Secondary Objectives: To assess the effect of a periodic fasting-mimicking diet on left ventricular ejection fraction, risk for arrhythmias, performance during exercise stress testing.

Study duration: 24 months; participant duration: 18 months (6 months intervention + 12 months follow up).

Trial Registration: German Register for Clinical Studies (DRKS): DRKS00019898

Status: Planned
Participant: 74 Patients with BMI 25-30 or > 30, between age > 18/ < 70 nonsusceptible to bariatric surgery; Estimated duration: 48 months.
Study: Interventional, Cross-over, Clinical Trial; [Anticipated Start Date: Jan 2020, Anticipated Stop Date: Jan 2022]
Location: Department of Clinical Sciences and Translational Medicine - ENT Unit, University of Rome Tor Vergata, ITER Center for Balance and Rehabilitation Research, Rome, Italy
Researcher: Alessandro Micarelli, MD, PhD (alessandromicarelli@yahoo.it), Marco Alessandrini, Beatrice Micarelli, Giovanni Cesana

Synopsis: The increase of body weight is actually associated with a reduction in olfactory sensitivity and it has been already demonstrated that body mass and fasting states may interact in order to influence the olfactory sensitivity. In particular, differences in terms of olfactory detection and threshold found between fasting and satiety periods have demonstrated to be mainly pronounced with the increase of body weight. Considering these aspects, it has been indicated that the gastric orexinergic peptide “GRELIN” behaves as an olfactory modulator between body weight and fasting state. Its receptor – indeed – is expressed in the olfactory bulb and central infusion of GRELIN have been demonstrated to increase the detection of odorants in rodents. At the same time obesity is associated with reduced hematic levels of GRELIN and it may modify the phasic suppression of this peptide after the meal even though this effect may vary depending on insulin sensitivity and macro-nutrient composition of the meal. Thus it has been further demonstrated that peripheral infusion of GRELIN increase the sniffing magnitude in healthy subjects and that BMI is associated to an higher influence of the internal state on the olfactory sensitivity and that these phenomena are partly due to a postprandial reactivity of GRELIN, which has been found altered in the obesity. Finally, as most important point, the blood infusion of this peptide in sated subjects increase the neuronal responses to food-related stimuli in cortical areas correlated to nutrition and reward, possibly contributing to the revaluation of food, mimicking a fasting state, since that such infusion also induce an exploratory sniffing in both animal and human models. Thus, given these experiences strengthening the association between olfactory sensitivity (and more in general olfactory behavior), which depose for an association between obesity, olfaction and craving/rewarding phenomena, the aim of the present study is to test if obese subjects – not included in surgical procedures - may benefit from a mimicking fasting protocol in order to modify their binge-eating behavior – by means of an unconscious olfactory re-arrangement – and thus benefit from a “spontaneous” weight reduction.

Patients will undergo one month before and one month after the implementation of FMD (lasting 6 months) - a battery of the following:

• Olfactory test
• Taste Test
• Neuropsychological tests: MMSE, TSK, HADS, DGI, usual gait speed, rapid gait speed, 400-m time, and Health ABC Physical Performance Battery (HABCPPB) score), total standing balance time, fine motor function (finger tapping time), and manual dexterity (Purdue Pegboard Test Termometro dello stress, California Verbal Learning Test [CVLT]), visuoperceptual speed (Digit Symbol Substitution Test [DSST]), executive function (Trail Making Test part B [TMT-B]), and attention (TMT-A)
• Blood Samples (IFOM – Milano)

Status: Ongoing
Participants: ProLon and Type 2 Diabetes; 100 individuals with type 2 diabetes and a BMI ≥ 27, who are treated with diet only and have a HbA1c > 48, or who are treated with diet and a dose of metformin
Study: Randomized, Controlled, Parallel Assignment, Assessor Blinded and Prospective Interventional Study (November 5, 2018 - December 31, 2021)
Location: Leiden University Medical Centre, Leiden, Netherlands
Researcher: Prof. Hanno Pijl (h.pijl@lumc.nl); Elske van den Burg, MD (e.l.van_den_burg@lumc.nl); Marjolein Schoonakker, MD (M.P.schoonakker@lumc.nl)

Synopsis: Calorie restriction is the most effective way to prevent and treat type 2 diabetes mellitus (DM2). It simultaneously ameliorates all metabolic anomalies that mark the disease, including hyperglycemia, dyslipidemia and hypertension. However, chronic restriction of food intake is extremely difficult to sustain for the vast majority of patients. Intermittent fasting exerts very similar metabolic effects, but total fasting on a regular basis may be even more difficult than chronic restriction of food intake and may also present safety challenges. There is an innovative, periodic 5-day plant-based dietary program (ProLon) that mimics and may even enhance the metabolic benefits of total fasting (despite considerable calorie content). It thus alleviates the burden of fasting while retaining its upsides. We hypothesize that intermittent use of this diet for 5 days every month will significantly improve the metabolic condition of patients with type 2 diabetes and diminish prescription drug use.

Trial registration: ClinicalTrials.gov -- NCT03811587

Status: Ongoing
Participants: 75 patients

Patients with mild to moderate ulcerative colitis (partial (non-endoscopic) Mayo Score 2-7) between the ages of 18-70. Patients must have elevated stool calprotectin and/or serum inflammatory marker levels (ESR and/or CRP).

Study: Randomized Interventional Pilot Study [Anticipated Start Date: March 2020]

Location: Division of Gastroenterology & Hepatology, Stanford University School of Medicine, San Francisco, CA

Researcher: Sidhartha R. Sinha, MD (sidsinha@stanford.edu)

Synopsis: We anticipate enrolling up to 75 patients total in this pilot study. Subjects will be randomized to a ​Fasting Mimicking Diet (FMD​) intervention or a control group. Patients in the intervention arm follow the FMD/ProLon diet (one 5-day diet per month for 3 months) that is commercially available with standardized daily meals and instructions consisting of FDA generally recognized as safe ingredients. Patients in the control arm will follow their regular diet.

A weekly questionnaire including dietary intake during periods of regular diet for both the FMD and control arm will also be provided, as well as a daily questionnaire during the FMD days of each cycle. Patients agreeing to optional colonoscopy/sigmoidoscopy will have this done at baseline and after the 3rd cycle.

Trial registration: ClinicalTrials.gov -- NCT03615690

Status: Planned
Participants: LKB1-inactive lung adenocarcinoma; 88 participants (18 to 75 years old)
Study: Randomized Clinical Trial
Location: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano        
Researcher: Marina Chiara Garassino, M.D. (marina.garassino@istitutotumori.mi.it); Lital Hollander (lital.hollander@marionegri.it); Claudio Vernieri, M.D., Ph.D (claudio.vernieri@istitutotumori.mi.it)

Synopsis: Lung cancer is one of the most common malignancies and tumor-related causes of death worldwide. In the last years, significant advances have occurred in the treatment of non-small cell lung cancer, in particular for the population of patients with a driver genetic mutation like EGFR, ALK or ROS1. For the remaining cases, the main novelty has been represented by immunotherapy, with anti-PD1/PDL1 agents having demonstrated a benefit over previous standard of care treatments, consisting platinum-based chemotherapy in first line and docetaxel in second line. Nonetheless, not all these patients are amenable to first-line immunotherapy, as only tumors expressing high PD-L1 levels seem to respond to these treatments. Lung adenocarcinoma with LKB1 mutations or macro/micro deletions has a particularly aggressive behavior and seems to be resistant to the effects of immunotherapy. Indeed, such a population appears to be disadvantaged as regards therapeutic options and requires the development of different approaches. LKB1 is involved in intracellular pathways that are crucial in the regulation of cancer cell metabolism. Metabolic reprogramming is a key step in tumorigenesis and several metabolic pathways, including glucose uptake and utilization, or lipid biosynthesis and utilization, are deregulated in cancer cells compared to their normal counterpart. Cells with hypo-active or inactive LKB1 are peculiar in that they show an exquisite vulnerability to energetic deprivation. Indeed, they are unable to survive when exposed to nutrient deprivation or drugs that affect cancer cell bioenergetics or specific metabolic processes. In particular, the class of drugs known as biguanides, which include the antidiabetic compound metformin, are able to inhibit mitochondrial metabolism and to reduce the intracellular concentration of ATP. Based on the well-known effects of metformin on cancer cell metabolism, as well as of preclinical evidence that demonstrate a synergism between cisplatin and metformin in lung cancer cell lines and animal models with LKB1 inactivation, the investigators hypothesize that combining standard platinum-based chemotherapy with metformin, with or without a low-calorie, low-carbohydrate, low-protein diet, also known as Fasting Mimicking Diet (FMD), may improve the efficacy of chemotherapy alone for the treatment of patients with LKB1-inactive lung adenocarcinoma.

To test this hypothesis, the investigators will perform an open label, randomized, phase II trial in which patients with advanced LKB1-inactive NSCLC will be randomized in a 1:1 way to receive standard-of-care platinum-pemetrexed chemotherapy plus metformin without (arm A) or with (Arm B) cyclic FMD, The primary study objective is to demonstrate that the experimental treatment (arm A plus arm B) improves median PFS from 7.6 months (historical control) to 12 months. Secondary study objectives will be to investigate the impact of the experimental treatment on overall survival, objective response rate, adverse events, systemic metabolic parameters (plasma glucose, amino acids, lipid profile).

Trial registration: ClinicalTrials.gov -- NCT03709147

Status: Planned
Participants: 25 overweight patients
Study: (Start Date: Jan 15, 2020; Anticipated End Date: Jan 15, 2022)
Location: Obesity and Comorbidities Research Center at University of Campinas (OCRC), San Paulo, Brazil
Researcher: Licio A. Velloso, MD, PhD

Synopsis: One of the research areas under investigation at OCRC deals with the characterization of mechanisms involved in beige/brown adipose tissue activation in humans. We would like to test the impact of 3-mo Prolon in a group of overweight/obese subjects and evaluate beige/brown adipose tissue using PET-CT scan, thermographic photographs, and a number of metabolic parameters related to thermogenesis. Our main objective is to evaluate the effect of a dietary intervention using Fasting Mimicking (FMD) on activation of beige/brown adipose tissue in humans.

Status: Completed
Participants: 102 participants; Healthy Individuals
Study: (Study Start Date: March 2013; Actual Primary Completion Date: June 2016; Actual Study Completion Date: June 2016)
Location: University of Southern California
Researcher: Min Wei, PhD

Published:

Brandhorst S, Choi IY, Wei M, et al. A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan. Cell Metab. 2015;22(1):86–99. doi:10.1016/j.cmet.2015.05.012

Wei M, Brandhorst S, Shelehchi M, et al. Fasting-mimicking diet and markers/risk factors for aging, diabetes, cancer, and cardiovascular disease. Sci Transl Med. 2017;9(377). doi:10.1126/scitranslmed.aai8700

Synopsis: Evidence from bio-gerontology research from our laboratory and others have showed that short-term fasting/starvation (STS) can improve the efficacy of chemotherapy by protecting normal cells and tissues and potentially sensitizing malignant cells to chemo drugs. Furthermore, STS improves risk factors associated with aging and age-related disease in rodent models. Prolonged fasting, however, is difficult to implement and may not be feasible or safe in humans. We have developed a fasting-mimicking diet (FMD) that was well accepted in a pilot human trial. The objective of the study is to ascertain the impact of the fasting-mimicking diet given to adult subjects for 5 days a month for 3 consecutive months. The investigators hypothesize that the specially designed dietary regimen can reduce the risk factors for metabolic syndrome and biomarkers associated with aging and age-related diseases.

Trial registration: ClinicalTrials.gov -- NCT02158897

Status: Completed
Participants: 48 participants with MS
Study: (Study Start Date: December 2011, Actual Primary Completion Date: February 2013; Actual Study Completion Date: January 2015)
Location: Charite University, Berlin, Germany
Researcher: Markus Bock, MD

Published: Choi IY, Piccio L, Childress P, et al. A Diet Mimicking Fasting Promotes Regeneration and Reduces Autoimmunity and Multiple Sclerosis Symptoms. Cell Rep. 2016;15(10):2136–2146. doi:10.1016/j.celrep.2016.05.009

Synopsis: It is well accepted that nutrition as an environmental factor is involved in the pathogenesis of multiple sclerosis. But is there a role for prolonged fasting and ketogenic low glycemic load treatment to alter the course of multiple sclerosis (MS)? The investigators think yes there is. Primarily the investigators want to detect if these diets are feasible for MS patients. Therefore the investigators examine the impact of this dietary intervention on the health related quality of life for individuals after 7 days, 3 months and 6 months in compare to baseline. Secondarily the investigators focus on endocrinological and immunological changes after 7 days, 3 months and 6 months in compare to baseline.

Trial registration: ClinicalTrials.gov -- NCT01538355