Clinical trial NCT03303534: Short-Term Endogenous Hydrogen Sulfide Upregulation
Official title: Short-Term Endogenous Hydrogen Sulfide Upregulation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Carotid Stenosis
Caloric Restriction
Keywords: inflammation
hydrogen sulfide
caloric restriction
vascular surgery
Lead sponsor: Brigham and Women's Hospital
Sponsor class: OTHER
First posted: 2017-10-06
Enrollment: 9
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 3:2 randomization to short-term protein calorie restriction diet versus regular meals prior to elective carotid artery endarterectomy
Primary purpose: BASIC_SCIENCE

Brief summary: This research study will compare the impact of dietary restriction pre-operatively before carotid endarterectomy compared to the standard nutrition that a patient typically eats. The investigators want to find out how patients comply and generally how well patients do with this type of dietary restriction before their surgery since animal studies suggest that short - term dietary restriction may be beneficial before surgery.

Detailed description: The primary, scientific long term objective is to study any correlation that brief upregulation of endogenous hydrogen sulfide (H2S) via pre-operative protein calorie restriction (PCR) in elective major surgery may have biologic effects in humans. In this study, the investigators plan to evaluate patient compliance and the physiologic response pre-operative PCR has on patients undergoing carotid endarterectomy surgery. This will be explored via two primary aims.

The First Aim looks to create a prospective, fast-track, one-year study of 40 vascular surgery patients undergoing elective carotid artery endarterectomy randomized into two pre-operative dietary groups: observational group (n=16) and PCR (commercially available ScandiShake x 3 days, n=24). This pilot study is based on preliminary data balanced with economic and clinical feasibility considerations. The primary endpoints of this study are: 1) feasibility of subject compliance with PCR (measured by direct dietary intake data and serum markers including plasma free amino acids and insulin-like growth factor; thus the 2:3 randomization) and 2) measurement of H2S and standard markers of stress before and after surgery (including stress hormones, oxidative stress, inflammation and cardiac troponin T levels). Individual patient's microbiomes,phenotype of circulating blood cells, adipose tissue (peri-vascular, subcutaneous), and the excised carotid plaque will be characterized to inform on potential mechanistic links among these and PCR induced H2S upregulation, reduced peri-operative stress, atherosclerotic plaque stability, and improved outcome (baseline and peri-procedural clinical datasets will be completed) for future clinical trials. Key secondary data points include observing endpoints such as carotid restenosis and surgical complications (cardiac, neurologic, wound, etc) between the two groups, which the investigators hypothesize will help to inform future trials. This pilot study will elucidate not only the practicality of pre-operative short term dietary restriction, but also provide physiologic data to support the long term primary scientific objective stated previously.

The Second Specific Aim is to establish a robust human discovery multi-institutional platform to capitalize on multiple aspects of this carefully constructed initiative toward long-term goals such as better understanding and translation of the biologic mechanisms of H2S and PCR. Data collected in the first aim across institutions will be integrated and made public.This platform will encourage communication and collaboration among basic scientists, translational investigators, and clinical communities. This synergy will allow the investigators to define the mechanisms of H2S and PCR effects, and will also give insights into the human response to trauma (lipidomics, microbiome, proteins/microRNAs) that regulate the pro-inflammatory response to injury, and will allow for mechanistic links among these factors ties to surgical outcomes.

Eligibility criteria: Inclusion Criteria:

* consenting adults (men and women)
* clinical indication for carotid endarterectomy (CEA) as determined by attending vascular surgeon
* if symptomatic, patients must be able to safely have surgery timed for PCR intervention

Exclusion Criteria:

* intolerance or allergy to any ingredients in the PCR diet (ScandiShake ingredients or almond milk/nuts)
* active infection
* pregnancy
* malnutrition determined by serum albumin lower than BWH reference value of 3.5 g/dL
* active drug dependency or alcoholism that could interfere with protocol adherence
* active non-cutaneous cancer under treatment with chemotherapeutic

Primary outcomes:
measure: subject compliance with PCR
timeFrame: three days pre-operatively
Secondary outcomes:
measure: measurement of local and systemic hydrogen sulfide and standard markers of stress peri-procedurally
timeFrame: change over 4.5 weeks from baseline
measure: fecal microbiome characterization
timeFrame: change over 4.5 weeks from baseline
Other outcomes:
Locations:
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
Study officials:
affiliation: Brigham and Women's Hospital
name: C. Keith Ozaki, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hine C, Kim HJ, Zhu Y, Harputlugil E, Longchamp A, Matos MS, Ramadoss P, Bauerle K, Brace L, Asara JM, Ozaki CK, Cheng SY, Singha S, Ahn KH, Kimmelman A, Fisher FM, Pissios P, Withers DJ, Selman C, Wang R, Yen K, Longo VD, Cohen P, Bartke A, Kopchick JJ, Miller R, Hollenberg AN, Mitchell JR. Hypothalamic-Pituitary Axis Regulates Hydrogen Sulfide Production. Cell Metab. 2017 Jun 6;25(6):1320-1333.e5. doi: 10.1016/j.cmet.2017.05.003.
citation: Longchamp A, Harputlugil E, Corpataux JM, Ozaki CK, Mitchell JR. Is Overnight Fasting before Surgery Too Much or Not Enough? How Basic Aging Research Can Guide Preoperative Nutritional Recommendations to Improve Surgical Outcomes: A Mini-Review. Gerontology. 2017;63(3):228-237. doi: 10.1159/000453109. Epub 2017 Jan 5.
citation: Longchamp A, Tao M, Bartelt A, Ding K, Lynch L, Hine C, Corpataux JM, Kristal BS, Mitchell JR, Ozaki CK. Surgical injury induces local and distant adipose tissue browning. Adipocyte. 2015 Nov 20;5(2):163-74. doi: 10.1080/21623945.2015.1111971. eCollection 2016 Apr-Jun.
citation: Robertson LT, Trevino-Villarreal JH, Mejia P, Grondin Y, Harputlugil E, Hine C, Vargas D, Zheng H, Ozaki CK, Kristal BS, Simpson SJ, Mitchell JR. Protein and Calorie Restriction Contribute Additively to Protection from Renal Ischemia Reperfusion Injury Partly via Leptin Reduction in Male Mice. J Nutr. 2015 Aug;145(8):1717-27. doi: 10.3945/jn.114.199380. Epub 2015 Jun 3.
citation: Hine C, Harputlugil E, Zhang Y, Ruckenstuhl C, Lee BC, Brace L, Longchamp A, Trevino-Villarreal JH, Mejia P, Ozaki CK, Wang R, Gladyshev VN, Madeo F, Mair WB, Mitchell JR. Endogenous hydrogen sulfide production is essential for dietary restriction benefits. Cell. 2015 Jan 15;160(1-2):132-44. doi: 10.1016/j.cell.2014.11.048. Epub 2014 Dec 23.
citation: Mauro CR, Tao M, Yu P, Trevino-Villerreal JH, Longchamp A, Kristal BS, Ozaki CK, Mitchell JR. Preoperative dietary restriction reduces intimal hyperplasia and protects from ischemia-reperfusion injury. J Vasc Surg. 2016 Feb;63(2):500-9.e1. doi: 10.1016/j.jvs.2014.07.004. Epub 2014 Aug 8.
citation: Nguyen B, Tao M, Yu P, Mauro C, Seidman MA, Wang YE, Mitchell J, Ozaki CK. Preoperative diet impacts the adipose tissue response to surgical trauma. Surgery. 2013 Apr;153(4):584-93. doi: 10.1016/j.surg.2012.11.001. Epub 2012 Dec 27.
citation: Mitchell JR, Beckman JA, Nguyen LL, Ozaki CK. Reducing elective vascular surgery perioperative risk with brief preoperative dietary restriction. Surgery. 2013 Apr;153(4):594-8. doi: 10.1016/j.surg.2012.09.007. Epub 2012 Dec 4.