Vascular DiseasesNCT05457881
Short-Term Endogenous Hydrogen Sulfide Upregulation For Vein Graft Disease
A study testing Scandi-Shake in people with Vascular Diseases and Surgery, run by Brigham and Women's Hospital at 1 site in United States.
Trial summary
A randomized, controlled trial to evaluate patient compliance and biologic mechanisms of a short-term pre-operative Protein-Calorie Restriction (PCR) diet in comparison to a normal ad libitum diet for 4 days before elective vascular surgery involving a major operation. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Vascular Diseases, Surgery
- What is being tested?
- Scandi-Shake
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 0 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Mar 2024to 1 Dec 2029
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 18 years of age or older
- Patients planned for non-emergency lower extremity vein bypass surgery
- Projected survival of at least one year
- Ability to provide informed consent
- Albumin ≥3.0 and negative pregnancy test (if relevant)
- No known allergy to Scandi-Shake ingredients
Who cannot join
- <18 years of age
- Emergency lower extremity vascular surgery
- Projected survival of < one year
- Albumin <3.0
- Pregnancy, intention to become pregnant, or lack of standard contraception method
- Allergy to Scandi-Shake ingredients
Trial locations and contacts
1 site in 1 country.
United States1 site
Brigham and Women's Hospital
Boston, Massachusetts, 02115
About this study
A randomized, controlled trial to evaluate patient compliance and biologic mechanisms of a short-term pre-operative Protein-Calorie Restriction (PCR) diet in comparison to a normal ad libitum diet for 4 days before elective vascular surgery involving a major operation. After a pilot study exploring the safety and feasibility of the PCR diet conducted inpatient before carotid endarterectomy titled Short-Term Endogenous Hydrogen Sulfide Upregulation, and a follow-up study titled Dietary Restriction in Vascular Surgery, the investigators now aim to expand the study to at home diet among a variety of vascular surgery procedures. This study will further elucidate not only the practicality of pre-operative short term dietary restriction, but also provide early data to inform biologic mechanisms and to inform future efficacy trails.
Read the detailed description
Peripheral arterial disease (PAD) remains a major health issue in the United States, especially with the metabolic syndrome and aging population. Surgical bypass using autogenous vein remains the most effective and durable choice for patients with advanced PAD. However, these vascular interventions suffer from high failure rates due to the development of significant occlusive lesions (intimal hyperplasia [IH]). Similar failure mechanisms plague coronary artery bypass grafts and endovascular interventions. Despite decades of vein graft research, our understanding of the biologic mechanisms of vein graft failure remains obscure.
Hydrogen sulfide (H2S) has emerged as a critical gaseous signaling molecule in multiple processes including ischemia/reperfusion (IR) injury, angiogenesis, intimal hyperplasia, and anti-inflammatory mechanisms. It even appears to hold anti-atherosclerotic properties. However, the gas is toxic with a half-life of minutes, and it can be rapidly oxidized. Furthermore, clinically useful pharmacologic H2S donors have not been developed to date. In our 2015 Cell paper the investigators link substantial upregulation of endogenous H2S via short-term manipulation of mammalian dietary intake: simple dietary restriction. Our first pilot study had aims to determine the feasibility and safety of a PCR diet in vascular patients, concluding with no significant serious adverse events in any of the patients receiving the diet. The investigators learned that patients do not like having to stay in the hospital research unit pre-operatively. Long term the investigators aim to substantively impact the vascular patient at several levels: protection from IR, intimal hyperplasia, peri-procedural events such as stroke, cardiac dysfunction and myocardial infarction, and promotion of angiogenesis. For the current effort, the investigators will focus on potential biologic mechanisms of PCR and feasibility of eventual larger initiatives to accomplish this long-term aim.
A powerful method to upregulate H2S is PCR. Defined as reduced food intake without malnutrition, PCR is best known for extending lifespan in model organisms from yeast to non-human primates. The efficacy of PCR against acute stress, including surgical stress, in preclinical models is also well established. Pilot studies suggest that humans respond to PCR in beneficial ways with respect to metabolic fitness (including improved glucose homeostasis, lipid profiles, and cardiovascular performance). But humans also have great difficulty complying with long-term voluntary food restriction, which is a prime reason that PCR has not been previously exploited in the clinical setting despite promising efficacy. However, recent data in model organisms point to a rapid onset of PCR benefits and challenges the notion that long-term PCR is required for benefits to accrue. In fruit flies, the maximal benefit of PCR on mortality risk occurs within 2-3 days. In rodents, the investigators have shown that surgical stress resistance also occurs within days, and the benefits center on upregulation of endogenous H2S. Nonetheless, except for pre-operative overnight fasting (which serves a different purpose) dietary recommendations are largely absent from peri-op management.
Pilot data suggest that adverse post-operative outcomes linked to oxidative stress, inflammation and stress hormones may be modified by brief PCR in humans as well. In subjects who undertook food restriction for 12 hours per day for a month, markers of inflammation decreased significantly. PCR has been shown to reduce oxidative stress in both chronic and acute settings. Similarly, PCR may decrease stress hormone release. PCR also appears to work rapidly even in obese individuals or ill individuals. In gastric bypass surgery, two weeks of PCR reduced the risk of complications and procedure difficulty. With respect to patient compliance, brief (4 days to 2 weeks) pre-operative dietary interventions have been shown to be feasible and safe in selected patients, ranging from obese candidates for laparoscopic surgery to living organ donors. In our own human pilot research, vascular surgery patients have safely completed 3 days of pre-operative PCR diet without serious adverse events or reactions.
For the current project the investigators propose a randomized, controlled trial to evaluate patient compliance and biologic effects of a short-term pre-operative PCR diet in comparison to a normal ad libitum diet for 4 days before elective vascular surgery involving an open major operation. This mechanistic clinical study is structured as a prospective, multi-year study of 226 vascular surgery patients undergoing non-emergency lower-extremity arterial vein bypass surgery randomized into two pre-operative dietary groups: observational group (n=90) and PCR (commercially available ScandiShake x 4 days, n=136). This specific dietary intervention to upregulate endogenous H2S is based on our preliminary data balanced with economic and clinical feasibility considerations. The event rate for the control group is assumed to be 33% based on the literature and data largely from our institutions. Our goal is to find a suitable (total) sample size for power 1 - β=0.8 at 5% level of significance. It has been assumed that Relative Risk Reduction (RRR) is 50% or Absolute Risk Reduction (ARR) is 16.5%. Projected total sample size, for treatment group to control group ratio of 1.5 (60% to 40%), is 225.55 which approximate to 226. For the structure of our dietary intervention this means 90 for the control group and 136 for the treatment group. However, it must be emphasized that the primary goal of this project is to decipher mechanisms in humans rather than evaluate clinical efficacy.
Employing this randomized (3:2), parallel design, subjects will be assigned to either the supervised PCR diet (Scandi-Shake [any of 4 flavors - vanilla, strawberry, banana cream, and caramel] mixed with almond milk (85 grams Scandi-Shake mix to 240 cc almond milk), calculated individually for a total daily volume to achieve 30% caloric restriction and 70% protein restriction, based on ideal body weight), or continued routine ad libitum diet. The Mifflin St.Jeor equation will be used to calculate the total 24-hour energy needs based on gender, age, height, weight, and activity factor for the PCR diet. Daily physical activity will be assessed by questionnaire to determine the activity factor for accurate calorie restriction calculations. Nutritionists will use this equation to create a unique shake for each individual patient. The entire course of the dietary intervention will occur only during the 4 days prior to surgery. The shakes will be separated into 4 equal portions per day, for a total of 16 portions across the 4 pre-operative days. Patients can consume the 4 daily portions at whichever time of day they choose. The shakes are frozen 24 hours before distribution. Water intake is ad libitum for both cohorts.
Subjects will be discretely randomized by the clinical research assistants upon final clearance for their procedure by the anesthesiology service, and their assigned group will be concealed to all subsequent team members (clinicians, research scientists, statistician) until data lock. Subjects in both cohorts will log their diet in the mobile application MealLogger. This app allows the subject to post a photo and short description of their food from a mobile device and directly share the information with the study coordinator. Staff can communicate through the app with subjects to clarify what exactly was eaten.
- Conditions
- Vascular Diseases, Surgery
- Being tested
- Scandi-Shake
- Medical subject headings
- Vascular Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Scandi-ShakeDietary supplement
Scandi-Shake [any of 4 flavors - vanilla, strawberry, banana cream, and caramel] mixed with almond milk (85 grams Scandi-Shake mix to 240 cc almond milk), calculated individually for a total daily volume to achieve 30% caloric restriction and 70% protein restriction, based on ideal body weight. The Mifflin St. Jeor equation will be used to calculate the total 24-hour energy needs based on gender, age, height, weight, and activity factor for the PCR diet. Daily physical activity will be assessed by questionnaire to determine the activity factor for accurate calorie restriction calculations. Nutritionists will use this equation to create a unique shake for each individual patient. The shakes will be separated into 4 equal portions per day, for a total of 16 portions across the 4 pre-operative days. Patients can consume the 4 daily portions at whichever time of day they choose. The shakes are frozen 24 hours before distribution.
| Study group | Role | What they receive |
|---|---|---|
| Protein-calorie restriction | Experimental | Four day dietary intervention immediately before surgery of Scandi-Shake [any of 4 flavors - vanilla, strawberry, banana cream, and caramel] mixed with almond milk (85 grams Scandi-Shake mix to 240 cc almond milk) calculated individually for a total daily volume to achieve 30% caloric restriction and 70% protein restriction, based on gender, age, height, weight, and activity level. Receives: Dietary Supplement: Scandi-Shake |
| Control | No intervention | Ad libitum diet for four days immediately before surgery |
What is being measured
The primary outcome is the main question the study is designed to answer.
Compliance with outpatient Protein-Calorie Restriction measured via food diary
Subject compliance with PCR will be measured through direct dietary intake data via food diary in comparison to the ad libitum diet. But one of the indirect goals of the initiative is to better understand how compliance can be assessed in this population.
Measured: 1 Month
Compliance with outpatient Protein-Calorie Restriction measured via biologic assays for plasma free amino acids
Subject compliance with PCR will be measured through biologic assays (e.g., plasma free amino acids) in comparison to the ad libitum diet. But one of the indirect goals of the initiative is to better understand how compliance can be assessed in this population.
Measured: 1 Month
Compliance with outpatient Protein-Calorie Restriction measured via biologic assays for pre-albumin
Subject compliance with PCR will be measured through biologic assays (e.g., insulin-like growth factor) in comparison to the ad libitum diet. But one of the indirect goals of the initiative is to better understand how compliance can be assessed in this population.
Measured: 1 Month
Compliance with outpatient Protein-Calorie Restriction measured via biologic assays insulin-like growth factor
Subject compliance with PCR will be measured through direct dietary intake data via food diary, and we will also have biologic assays for serum markers including plasma free amino acids, pre-albumin, and insulin-like growth factor in comparison to the ad libitum diet. But, one of the indirect goals of the initiative is to better understand how compliance can be assessed in this population.
Measured: 1 Month
Change over time from baseline values to values before surgery and day 1 after surgery in the comparison of H2S and standard biological markers of stress in blood
H2S and standard biological markers of stress are collected at baseline, immediately before surgery, and day 1 after surgery. Biological markers include: adipose phenotyping (quantification of adipokines, adipose derived hormones), leukocyte phenotyping and quantification via flow cytometry, and serum assays of IL-1beta, IL-6, IL-8, HGF, leptin, MCP-1, PAI-1, resistin, NGF, TNF, adiponectin, hydrogen sulfide (including production capacity) assays, insulin, lipid panels, FGF 21, pre-albumin, epinephrine, norepinephrine, dopamine, CBC with differential, basic metabolic panel including calcium. These biomarkers will be quantified in the various tissues for individual participants and be mathematically aggregated for groups (i.e., an aggregate unit of measurement will be used)"
Measured: Baseline, Day 0, Day 1
Major Adverse Limb Event
Untreated loss of conduit patency and/or severe limb ischemia leading to an intervention or major amputation. Includes acute limb ischemia (including the need for thrombectomy/ thrombolysis), major amputation (above the ankle), need for re-do surgical revascularization for the index limb.
Measured: 2 years
Secondary outcomes (4)
Comparison of surgical and medical complications
These endpoints will include surgical and medical complications such as cardiac, neurologic, infectious, vascular, wound, and any other clinically significant events that occur within 30 days of surgery
Measured: 1 Month
One-year survival
Patient survival after one-year participating in the trial
Measured: 1 year
Renal dysfunction, stroke, myocardial infarction, patency of the vein graft (primary, primary assisted, secondary), survival.
Medical record derived complications (using standardized NSQIP definitions and outcomes) +/- PCR. eGFR will be the primary measure of renal function.
These data will be integrated mathematically to combine all the features in an additive model to develop the final integrative model.
Measured: 1 Month, 1 year
Wound Complication
Superficial Surgical Site Infection (SSI): Infection that involves only skin/ SQ tissue of the incision and at least one of the following: Purulent drainage, Positive wound culture, At least one of the following signs/symptoms of infection: pain or tenderness, localized swelling, redness, or heat AND superficial incision is deliberately opened by the surgeon, unless incision is culture-negative, Diagnosis of superficial SSI by attending Deep SSI: Infection involves deep tissues (fascial/ muscle layers) of the incision and at least one of the following: Purulent drainage from the deep incision, A deep incision spontaneously dehisces or is deliberately opened by a surgeon when the patient has at least one of the following signs or symptoms: fever (> 38C), localized pain, or tenderness, unless site is culture-negative, An abscess or other evidence of infection involving the deep incision, Diagnosis of deep SSI by attending Dehiscence: Skin separation requiring local wound care.
Measured: 1 Month
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Jul 2022
- Study start1 Mar 2024 (estimated)
- Primary completion1 Mar 2029 (estimated)
- Study completion1 Dec 2029 (estimated)
Why it stopped: Insufficient funds to start study
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (95)Papers the sponsor has linked to this study.
- Other trials for Vascular DiseasesStudies of the same condition, open and under way.
- More trials run by Brigham and Women's HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- 3:2 randomization to short-term protein calorie restriction diet versus regular meals prior to elective major vascular surgery
- Masking
- Double blind
- Who is masked
- Investigator, Outcomes assessor
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- Brigham and Women's Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, C. Keith Ozaki, M.D., F.A.C.S., Brigham and Women's Hospital
- Investigators
- Charles K Ozaki, MD, Principal investigator, Brigham and Women's Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05457881
- Sponsor's protocol ID
- 2021P002206
- Status last verified
- Sep 2025
- First submitted
- 7 Feb 2022
- Last updated
- 18 Sep 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, Dai S, Ford ES, Fox CS, Franco S, Fullerton HJ, Gillespie C, Hailpern SM, Heit JA, Howard VJ, Huffman MD, Judd SE, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Mackey RH, Magid DJ, Marcus GM, Marelli A, Matchar DB, McGuire DK, Mohler ER 3rd, Moy CS, Mussolino ME, Neumar RW, Nichol G, Pandey DK, Paynter NP, Reeves MJ, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Wong ND, Woo D, Turner MB; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics--2014 update: a report from the American Heart Association. Circulation. 2014 Jan 21;129(3):e28-e292. doi: 10.1161/01.cir.0000441139.02102.80. Epub 2013 Dec 18. No abstract available.
PubMed 24352519Kraiss LW, Conte MS, Geary RL, Kibbe M, Ozaki CK. Setting high-impact clinical research priorities for the Society for Vascular Surgery. J Vasc Surg. 2013 Feb;57(2):493-500. doi: 10.1016/j.jvs.2012.09.069.
PubMed 23337859Adam DJ, Beard JD, Cleveland T, Bell J, Bradbury AW, Forbes JF, Fowkes FG, Gillepsie I, Ruckley CV, Raab G, Storkey H; BASIL trial participants. Bypass versus angioplasty in severe ischaemia of the leg (BASIL): multicentre, randomised controlled trial. Lancet. 2005 Dec 3;366(9501):1925-34. doi: 10.1016/S0140-6736(05)67704-5.
PubMed 16325694Bradbury AW. Bypass versus angioplasty in severe ischaemia of the leg (BASIL) trial: what are its implications? Semin Vasc Surg. 2009 Dec;22(4):267-74. doi: 10.1053/j.semvascsurg.2009.10.010.
PubMed 20006808Bradbury AW; BASIL trial Investigators and Participants. Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial in perspective. J Vasc Surg. 2010 May;51(5 Suppl):1S-4S. doi: 10.1016/j.jvs.2010.02.002. No abstract available.
PubMed 20435257Forbes JF, Adam DJ, Bell J, Fowkes FG, Gillespie I, Raab GM, Ruckley CV, Bradbury AW; BASIL trial Participants. Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial: Health-related quality of life outcomes, resource utilization, and cost-effectiveness analysis. J Vasc Surg. 2010 May;51(5 Suppl):43S-51S. doi: 10.1016/j.jvs.2010.01.076.
PubMed 20435261Bradbury AW, Adam DJ, Bell J, Forbes JF, Fowkes FG, Gillespie I, Raab G, Ruckley CV. Multicentre randomised controlled trial of the clinical and cost-effectiveness of a bypass-surgery-first versus a balloon-angioplasty-first revascularisation strategy for severe limb ischaemia due to infrainguinal disease. The Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial. Health Technol Assess. 2010 Mar;14(14):1-210, iii-iv. doi: 10.3310/hta14140.
PubMed 20307380Bradbury AW, Adam DJ, Bell J, Forbes JF, Fowkes FG, Gillespie I, Ruckley CV, Raab GM; BASIL trial Participants. Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial: An intention-to-treat analysis of amputation-free and overall survival in patients randomized to a bypass surgery-first or a balloon angioplasty-first revascularization strategy. J Vasc Surg. 2010 May;51(5 Suppl):5S-17S. doi: 10.1016/j.jvs.2010.01.073.
PubMed 20435258Conte MS, Bandyk DF, Clowes AW, Moneta GL, Seely L, Lorenz TJ, Namini H, Hamdan AD, Roddy SP, Belkin M, Berceli SA, DeMasi RJ, Samson RH, Berman SS; PREVENT III Investigators. Results of PREVENT III: a multicenter, randomized trial of edifoligide for the prevention of vein graft failure in lower extremity bypass surgery. J Vasc Surg. 2006 Apr;43(4):742-751; discussion 751. doi: 10.1016/j.jvs.2005.12.058.
PubMed 16616230Ozaki CK. Cytokines and the early vein graft: strategies to enhance durability. J Vasc Surg. 2007 Jun;45 Suppl A(Suppl A):A92-8. doi: 10.1016/j.jvs.2007.02.032.
PubMed 17544029Conte MS. Technical factors in lower-extremity vein bypass surgery: how can we improve outcomes? Semin Vasc Surg. 2009 Dec;22(4):227-33. doi: 10.1053/j.semvascsurg.2009.10.004.
PubMed 20006802Conte MS, Bandyk DF, Clowes AW, Moneta GL, Namini H, Seely L. Risk factors, medical therapies and perioperative events in limb salvage surgery: observations from the PREVENT III multicenter trial. J Vasc Surg. 2005 Sep;42(3):456-64; discussion 464-5. doi: 10.1016/j.jvs.2005.05.001.
PubMed 16171587Conte MS, Mann MJ, Simosa HF, Rhynhart KK, Mulligan RC. Genetic interventions for vein bypass graft disease: a review. J Vasc Surg. 2002 Nov;36(5):1040-52. doi: 10.1067/mva.2002.129112.
PubMed 12422116Schleifenbaum J, Kohn C, Voblova N, Dubrovska G, Zavarirskaya O, Gloe T, Crean CS, Luft FC, Huang Y, Schubert R, Gollasch M. Systemic peripheral artery relaxation by KCNQ channel openers and hydrogen sulfide. J Hypertens. 2010 Sep;28(9):1875-82. doi: 10.1097/HJH.0b013e32833c20d5.
PubMed 20577128Polhemus D, Kondo K, Bhushan S, Bir SC, Kevil CG, Murohara T, Lefer DJ, Calvert JW. Hydrogen sulfide attenuates cardiac dysfunction after heart failure via induction of angiogenesis. Circ Heart Fail. 2013 Sep 1;6(5):1077-86. doi: 10.1161/CIRCHEARTFAILURE.113.000299. Epub 2013 Jun 28.
PubMed 23811964
Study at a glance
From the registry record, last updated by the sponsor on 18 Sep 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Short-Term Endogenous Hydrogen Sulfide Upregulation For Vein Graft Disease
- ClinicalTrials.gov ID
- NCT05457881
- Acronym / sponsor ID
- 2021P002206
- Conditions
- Vascular Diseases, Surgery
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: Insufficient funds to start study
- Enrolment
- 0 participants (actual)
- Lead sponsor
- Brigham and Women's HospitalUniversity, hospital or other
- Study start
- 1 Mar 2024 (estimated)
- Primary completion
- 1 Mar 2029 (estimated)
- Study completion
- 1 Dec 2029 (estimated)
- First posted
- 14 Jul 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
A randomized, controlled trial to evaluate patient compliance and biologic mechanisms of a short-term pre-operative Protein-Calorie Restriction (PCR) diet in comparison to a normal ad libitum diet for 4 days before elective vascular surgery involving a major operation. After a pilot study exploring the safety and feasibility of the PCR diet conducted inpatient before carotid endarterectomy titled Short-Term Endogenous Hydrogen Sulfide Upregulation, and a follow-up study titled Dietary Restriction in Vascular Surgery, the investigators now aim to expand the study to at home diet among a variety of vascular surgery procedures. This study will further elucidate not only the practicality of pre-operative short term dietary restriction, but also provide early data to inform biologic mechanisms and to inform future efficacy trails.
Detailed description
Peripheral arterial disease (PAD) remains a major health issue in the United States, especially with the metabolic syndrome and aging population. Surgical bypass using autogenous vein remains the most effective and durable choice for patients with advanced PAD. However, these vascular interventions suffer from high failure rates due to the development of significant occlusive lesions (intimal hyperplasia [IH]). Similar failure mechanisms plague coronary artery bypass grafts and endovascular interventions. Despite decades of vein graft research, our understanding of the biologic mechanisms of vein graft failure remains obscure.
Hydrogen sulfide (H2S) has emerged as a critical gaseous signaling molecule in multiple processes including ischemia/reperfusion (IR) injury, angiogenesis, intimal hyperplasia, and anti-inflammatory mechanisms. It even appears to hold anti-atherosclerotic properties. However, the gas is toxic with a half-life of minutes, and it can be rapidly oxidized. Furthermore, clinically useful pharmacologic H2S donors have not been developed to date. In our 2015 Cell paper the investigators link substantial upregulation of endogenous H2S via short-term manipulation of mammalian dietary intake: simple dietary restriction. Our first pilot study had aims to determine the feasibility and safety of a PCR diet in vascular patients, concluding with no significant serious adverse events in any of the patients receiving the diet. The investigators learned that patients do not like having to stay in the hospital research unit pre-operatively. Long term the investigators aim to substantively impact the vascular patient at several levels: protection from IR, intimal hyperplasia, peri-procedural events such as stroke, cardiac dysfunction and myocardial infarction, and promotion of angiogenesis. For the current effort, the investigators will focus on potential biologic mechanisms of PCR and feasibility of eventual larger initiatives to accomplish this long-term aim.
A powerful method to upregulate H2S is PCR. Defined as reduced food intake without malnutrition, PCR is best known for extending lifespan in model organisms from yeast to non-human primates. The efficacy of PCR against acute stress, including surgical stress, in preclinical models is also well established. Pilot studies suggest that humans respond to PCR in beneficial ways with respect to metabolic fitness (including improved glucose homeostasis, lipid profiles, and cardiovascular performance). But humans also have great difficulty complying with long-term voluntary food restriction, which is a prime reason that PCR has not been previously exploited in the clinical setting despite promising efficacy. However, recent data in model organisms point to a rapid onset of PCR benefits and challenges the notion that long-term PCR is required for benefits to accrue. In fruit flies, the maximal benefit of PCR on mortality risk occurs within 2-3 days. In rodents, the investigators have shown that surgical stress resistance also occurs within days, and the benefits center on upregulation of endogenous H2S. Nonetheless, except for pre-operative overnight fasting (which serves a different purpose) dietary recommendations are largely absent from peri-op management.
Pilot data suggest that adverse post-operative outcomes linked to oxidative stress, inflammation and stress hormones may be modified by brief PCR in humans as well. In subjects who undertook food restriction for 12 hours per day for a month, markers of inflammation decreased significantly. PCR has been shown to reduce oxidative stress in both chronic and acute settings. Similarly, PCR may decrease stress hormone release. PCR also appears to work rapidly even in obese individuals or ill individuals. In gastric bypass surgery, two weeks of PCR reduced the risk of complications and procedure difficulty. With respect to patient compliance, brief (4 days to 2 weeks) pre-operative dietary interventions have been shown to be feasible and safe in selected patients, ranging from obese candidates for laparoscopic surgery to living organ donors. In our own human pilot research, vascular surgery patients have safely completed 3 days of pre-operative PCR diet without serious adverse events or reactions.
For the current project the investigators propose a randomized, controlled trial to evaluate patient compliance and biologic effects of a short-term pre-operative PCR diet in comparison to a normal ad libitum diet for 4 days before elective vascular surgery involving an open major operation. This mechanistic clinical study is structured as a prospective, multi-year study of 226 vascular surgery patients undergoing non-emergency lower-extremity arterial vein bypass surgery randomized into two pre-operative dietary groups: observational group (n=90) and PCR (commercially available ScandiShake x 4 days, n=136). This specific dietary intervention to upregulate endogenous H2S is based on our preliminary data balanced with economic and clinical feasibility considerations. The event rate for the control group is assumed to be 33% based on the literature and data largely from our institutions. Our goal is to find a suitable (total) sample size for power 1 - β=0.8 at 5% level of significance. It has been assumed that Relative Risk Reduction (RRR) is 50% or Absolute Risk Reduction (ARR) is 16.5%. Projected total sample size, for treatment group to control group ratio of 1.5 (60% to 40%), is 225.55 which approximate to 226. For the structure of our dietary intervention this means 90 for the control group and 136 for the treatment group. However, it must be emphasized that the primary goal of this project is to decipher mechanisms in humans rather than evaluate clinical efficacy.
Employing this randomized (3:2), parallel design, subjects will be assigned to either the supervised PCR diet (Scandi-Shake [any of 4 flavors - vanilla, strawberry, banana cream, and caramel] mixed with almond milk (85 grams Scandi-Shake mix to 240 cc almond milk), calculated individually for a total daily volume to achieve 30% caloric restriction and 70% protein restriction, based on ideal body weight), or continued routine ad libitum diet. The Mifflin St.Jeor equation will be used to calculate the total 24-hour energy needs based on gender, age, height, weight, and activity factor for the PCR diet. Daily physical activity will be assessed by questionnaire to determine the activity factor for accurate calorie restriction calculations. Nutritionists will use this equation to create a unique shake for each individual patient. The entire course of the dietary intervention will occur only during the 4 days prior to surgery. The shakes will be separated into 4 equal portions per day, for a total of 16 portions across the 4 pre-operative days. Patients can consume the 4 daily portions at whichever time of day they choose. The shakes are frozen 24 hours before distribution. Water intake is ad libitum for both cohorts.
Subjects will be discretely randomized by the clinical research assistants upon final clearance for their procedure by the anesthesiology service, and their assigned group will be concealed to all subsequent team members (clinicians, research scientists, statistician) until data lock. Subjects in both cohorts will log their diet in the mobile application MealLogger. This app allows the subject to post a photo and short description of their food from a mobile device and directly share the information with the study coordinator. Staff can communicate through the app with subjects to clarify what exactly was eaten.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- 3:2 randomization to short-term protein calorie restriction diet versus regular meals prior to elective major vascular surgery
| Arm | Type | Receives |
|---|---|---|
| Protein-calorie restriction | Experimental | Dietary Supplement: Scandi-ShakeFour day dietary intervention immediately before surgery of Scandi-Shake [any of 4 flavors - vanilla, strawberry, banana cream, and caramel] mixed with almond milk (85 grams Scandi-Shake mix to 240 cc almond milk) calculated individually for a total daily volume to achieve 30% caloric restriction and 70% protein restriction, based on gender, age, height, weight, and activity level. |
| Control | No intervention | –Ad libitum diet for four days immediately before surgery |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- 18 years of age or older
- Patients planned for non-emergency lower extremity vein bypass surgery
- Projected survival of at least one year
- Ability to provide informed consent
- Albumin ≥3.0 and negative pregnancy test (if relevant)
Key exclusion criteria (6 listed)
- <18 years of age
- Emergency lower extremity vascular surgery
- Projected survival of < one year
- Albumin <3.0
- Pregnancy, intention to become pregnant, or lack of standard contraception method
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Scandi-ShakeScandi-Shake [any of 4 flavors - vanilla, strawberry, banana cream, and caramel] mixed with almond milk (85 grams Scandi-Shake mix to 240 cc almond milk), calculated individually for a total daily volume to achieve 30% caloric restriction and 70% protein restriction, based on ideal body weight. The Mifflin St. Jeor equation will be used to calculate the total 24-hour energy needs based on gender, age, height, weight, and activity factor for the PCR diet. Daily physical activity will be assessed by questionnaire to determine the activity factor for accurate calorie restriction calculations. Nutritionists will use this equation to create a unique shake for each individual patient. The shakes will be separated into 4 equal portions per day, for a total of 16 portions across the 4 pre-operative days. Patients can consume the 4 daily portions at whichever time of day they choose. The shakes are frozen 24 hours before distribution. | Dietary supplement | Protein-calorie restriction |
Primary outcome
Compliance with outpatient Protein-Calorie Restriction measured via food diary
Time frame: 1 Month
Subject compliance with PCR will be measured through direct dietary intake data via food diary in comparison to the ad libitum diet. But one of the indirect goals of the initiative is to better understand how compliance can be assessed in this population.
Compliance with outpatient Protein-Calorie Restriction measured via biologic assays for plasma free amino acids
Time frame: 1 Month
Subject compliance with PCR will be measured through biologic assays (e.g., plasma free amino acids) in comparison to the ad libitum diet. But one of the indirect goals of the initiative is to better understand how compliance can be assessed in this population.
Compliance with outpatient Protein-Calorie Restriction measured via biologic assays for pre-albumin
Time frame: 1 Month
Subject compliance with PCR will be measured through biologic assays (e.g., insulin-like growth factor) in comparison to the ad libitum diet. But one of the indirect goals of the initiative is to better understand how compliance can be assessed in this population.
Compliance with outpatient Protein-Calorie Restriction measured via biologic assays insulin-like growth factor
Time frame: 1 Month
Subject compliance with PCR will be measured through direct dietary intake data via food diary, and we will also have biologic assays for serum markers including plasma free amino acids, pre-albumin, and insulin-like growth factor in comparison to the ad libitum diet. But, one of the indirect goals of the initiative is to better understand how compliance can be assessed in this population.
Change over time from baseline values to values before surgery and day 1 after surgery in the comparison of H2S and standard biological markers of stress in blood
Time frame: Baseline, Day 0, Day 1
H2S and standard biological markers of stress are collected at baseline, immediately before surgery, and day 1 after surgery. Biological markers include: adipose phenotyping (quantification of adipokines, adipose derived hormones), leukocyte phenotyping and quantification via flow cytometry, and serum assays of IL-1beta, IL-6, IL-8, HGF, leptin, MCP-1, PAI-1, resistin, NGF, TNF, adiponectin, hydrogen sulfide (including production capacity) assays, insulin, lipid panels, FGF 21, pre-albumin, epinephrine, norepinephrine, dopamine, CBC with differential, basic metabolic panel including calcium. These biomarkers will be quantified in the various tissues for individual participants and be mathematically aggregated for groups (i.e., an aggregate unit of measurement will be used)"
Major Adverse Limb Event
Time frame: 2 years
Untreated loss of conduit patency and/or severe limb ischemia leading to an intervention or major amputation. Includes acute limb ischemia (including the need for thrombectomy/ thrombolysis), major amputation (above the ankle), need for re-do surgical revascularization for the index limb.
4 secondary outcomes
Comparison of surgical and medical complications
Time frame: 1 Month
One-year survival
Time frame: 1 year
Renal dysfunction, stroke, myocardial infarction, patency of the vein graft (primary, primary assisted, secondary), survival.
Time frame: 1 Month, 1 year
Wound Complication
Time frame: 1 Month
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Sep 2025.
- Background: PubMed 24352519Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, Dai S, Ford ES, Fox CS, Franco S, Fullerton HJ, Gillespie C, Hailpern SM, Heit JA, Howard VJ, Huffman MD, Judd SE, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Mackey RH, Magid DJ, Marcus GM, Marelli A, Matchar DB, McGuire DK, Mohler ER 3rd, Moy CS, Mussolino ME, Neumar RW, Nichol G, Pandey DK, Paynter NP, Reeves MJ, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Wong ND, Woo D, Turner MB; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics--2014 update: a report from the American Heart Association. Circulation. 2014 Jan 21;129(3):e28-e292. doi: 10.1161/01.cir.0000441139.02102.80. Epub 2013 Dec 18. No abstract available.
- Background: PubMed 23337859Kraiss LW, Conte MS, Geary RL, Kibbe M, Ozaki CK. Setting high-impact clinical research priorities for the Society for Vascular Surgery. J Vasc Surg. 2013 Feb;57(2):493-500. doi: 10.1016/j.jvs.2012.09.069.
- Background: PubMed 16325694Adam DJ, Beard JD, Cleveland T, Bell J, Bradbury AW, Forbes JF, Fowkes FG, Gillepsie I, Ruckley CV, Raab G, Storkey H; BASIL trial participants. Bypass versus angioplasty in severe ischaemia of the leg (BASIL): multicentre, randomised controlled trial. Lancet. 2005 Dec 3;366(9501):1925-34. doi: 10.1016/S0140-6736(05)67704-5.
- Background: PubMed 20006808Bradbury AW. Bypass versus angioplasty in severe ischaemia of the leg (BASIL) trial: what are its implications? Semin Vasc Surg. 2009 Dec;22(4):267-74. doi: 10.1053/j.semvascsurg.2009.10.010.
- Background: PubMed 20435257Bradbury AW; BASIL trial Investigators and Participants. Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial in perspective. J Vasc Surg. 2010 May;51(5 Suppl):1S-4S. doi: 10.1016/j.jvs.2010.02.002. No abstract available.
- Background: PubMed 20435261Forbes JF, Adam DJ, Bell J, Fowkes FG, Gillespie I, Raab GM, Ruckley CV, Bradbury AW; BASIL trial Participants. Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial: Health-related quality of life outcomes, resource utilization, and cost-effectiveness analysis. J Vasc Surg. 2010 May;51(5 Suppl):43S-51S. doi: 10.1016/j.jvs.2010.01.076.
- Background: PubMed 20307380Bradbury AW, Adam DJ, Bell J, Forbes JF, Fowkes FG, Gillespie I, Raab G, Ruckley CV. Multicentre randomised controlled trial of the clinical and cost-effectiveness of a bypass-surgery-first versus a balloon-angioplasty-first revascularisation strategy for severe limb ischaemia due to infrainguinal disease. The Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial. Health Technol Assess. 2010 Mar;14(14):1-210, iii-iv. doi: 10.3310/hta14140.
- Background: PubMed 20435258Bradbury AW, Adam DJ, Bell J, Forbes JF, Fowkes FG, Gillespie I, Ruckley CV, Raab GM; BASIL trial Participants. Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial: An intention-to-treat analysis of amputation-free and overall survival in patients randomized to a bypass surgery-first or a balloon angioplasty-first revascularization strategy. J Vasc Surg. 2010 May;51(5 Suppl):5S-17S. doi: 10.1016/j.jvs.2010.01.073.
- Background: PubMed 16616230Conte MS, Bandyk DF, Clowes AW, Moneta GL, Seely L, Lorenz TJ, Namini H, Hamdan AD, Roddy SP, Belkin M, Berceli SA, DeMasi RJ, Samson RH, Berman SS; PREVENT III Investigators. Results of PREVENT III: a multicenter, randomized trial of edifoligide for the prevention of vein graft failure in lower extremity bypass surgery. J Vasc Surg. 2006 Apr;43(4):742-751; discussion 751. doi: 10.1016/j.jvs.2005.12.058.
- Background: PubMed 17544029Ozaki CK. Cytokines and the early vein graft: strategies to enhance durability. J Vasc Surg. 2007 Jun;45 Suppl A(Suppl A):A92-8. doi: 10.1016/j.jvs.2007.02.032.
- Background: PubMed 20006802Conte MS. Technical factors in lower-extremity vein bypass surgery: how can we improve outcomes? Semin Vasc Surg. 2009 Dec;22(4):227-33. doi: 10.1053/j.semvascsurg.2009.10.004.
- Background: PubMed 16171587Conte MS, Bandyk DF, Clowes AW, Moneta GL, Namini H, Seely L. Risk factors, medical therapies and perioperative events in limb salvage surgery: observations from the PREVENT III multicenter trial. J Vasc Surg. 2005 Sep;42(3):456-64; discussion 464-5. doi: 10.1016/j.jvs.2005.05.001.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Charles K Ozaki, MD principal investigator
Brigham and Women's Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Scandi-Shake in people with Vascular Diseases and Surgery, run by Brigham and Women's Hospital at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 18 Sep 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Compliance with outpatient Protein-Calorie Restriction measured via food diary (time frame: 1 Month). The study lists 6 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05457881, which also lists 95 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Sep 2025.