Cholecalciferol Supplementation for Sepsis in the ICU (CSI)

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 2014 by Massachusetts General Hospital
Sponsor:
Information provided by (Responsible Party):
Sadeq A. Quraishi, Massachusetts General Hospital
ClinicalTrials.gov Identifier:
NCT01896544
First received: July 8, 2013
Last updated: February 23, 2014
Last verified: February 2014
  Purpose

Sepsis in a clinical entity that occurs in patients with serious infections. Though the severity of illness may vary, every year, approximately 1.6 million Americans are treated for sepsis. Even with timely interventions, anywhere from 16% to >80% of patients with sepsis will not survive. Immune dysfunction is thought to play a critical role in the ability for infections to evolve into sepsis and to eventually lead to death. Recently, vitamin D has been identified as a key regulator of the immune system. While it remains unclear whether optimizing vitamin D status may improve outcomes in sepsis, little is known about the effects of vitamin D supplementation in patients with severe infections. As such, our goal is to study whether high doses of cholecalciferol (vitamin D3) can improve vitamin D status and boost certain aspects of the immune system in patients with sepsis.


Condition Intervention Phase
Hypovitaminosis D
Dietary Supplement: Cholecalciferol
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: The Effect of Cholecalciferol Supplementation on Vitamin D Status in Sepsis

Resource links provided by NLM:


Further study details as provided by Massachusetts General Hospital:

Primary Outcome Measures:
  • Change in vitamin D status 7 days following supplementation with cholecalciferol [ Time Frame: Patients will be followed between the onset of suspected sepsis and for an average duration of 7 days ] [ Designated as safety issue: Yes ]
    Subjects will receive 200,000 IU or 400,000 IU cholecalciferol suspension (vs. placebo) within 24 hours from the onset of a suspected case of sepsis during their hospitalization. Vitamin D status at the onset of a suspected case of sepsis will be compared to vitamin D status between 5-9 days after supplementation with cholecalciferol or placebo. To assess vitamin D status, we will measure serum and urine: 1) 25-hydroxyvitamin D; 2) 1,25-dihydroxyvitamin D; 3) 24,25-dihydroxyvitamin D; 4) Fibroblast growth factor 23; 5) Vitamin D binding protein; 6) LL-37; 7) Parathyroid hormone; 8) Albumin; 9) Calcium; and 10) Phosphorus levels.


Secondary Outcome Measures:
  • Change in immunological profile 7 days following supplementation with cholecalciferol [ Time Frame: Patients will be followed between the onset of suspected sepsis and for an average duration of 7 days ] [ Designated as safety issue: No ]
    Subjects will receive 200,000 IU or 400,000 IU cholecalciferol suspension (vs. placebo) within 24 hours from the onset of a suspected case of sepsis during their hospitalization. Immunological profile at the onset of a suspected case of sepsis will be compared to the immunological profile between 5-9 days after supplementation with cholecalciferol or placebo. To assess the immunological profile, we will measure serum: 1) Complete blood count with a differential; 2) T-cell subsets and migration; and 3) Cytokines.


Other Outcome Measures:
  • Incidence of infection-related complications within 90 days from the onset of a suspected case of sepsis [ Time Frame: Patients will be followed between the onset of suspected sepsis and for an average duration of 90 days ] [ Designated as safety issue: No ]
    Subjects will receive 200,000 IU or 400,000 IU cholecalciferol suspension (vs. placebo) within 24 hours from the onset of a suspected case of sepsis during their hospitalization. The incidence of infection-related complications will be assessed between the onset of suspected sepsis and 80-100 days after supplementation with cholecalciferol or placebo. To assess the incidence of infection-related complications, we will measure rates of: 1) vasopressor requirements; 2) acute co-morbidities (e.g. myocardial infarction, cerebrovascular accident, acute renal failure); 3) recurrent infections; 4) ICU length of stay; 5) hospital length of stay; 6) ICU readmission; 7) hospital readmission; and 8) mortality.


Estimated Enrollment: 30
Study Start Date: January 2014
Estimated Study Completion Date: March 2014
Estimated Primary Completion Date: March 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Cholecalciferol Dose II
Oral suspension cholecalciferol 400,000 IU
Dietary Supplement: Cholecalciferol
Placebo Comparator: Placebo
Active Comparator: Cholecalciferol Dose I
Oral suspension cholecalciferol 200,000 IU
Dietary Supplement: Cholecalciferol

Detailed Description:

Sepsis is a clinical syndrome that complicates severe infections. It is characterized by the cardinal signs of inflammation (e.g. vasodilation, leukocytosis, increased microvascular permeability) occurring in tissues that are remote from the site of an infection. Current theories about the onset and progression of the sepsis syndrome focus on dysregulation of inflammatory responses, including the possibility that a massive and uncontrolled release of pro-inflammatory mediators initiates a chain of events that lead to widespread tissue injury. The degree of immune dysfunction is thought to correlate with the severity of the sepsis syndrome. Sepsis syndrome can range from sepsis, to severe sepsis, septic shock, and multiple organ dysfunction syndrome (MODS). The mortality associated with each of these is estimated to be 16%, 20%, 46%, >80%, respectively. The annual incidence of sepsis syndrome exceeds 1.6 million cases in the United States alone.

Recently, cells of the innate and adaptive immune system have been shown to express the vitamin D receptor. Vitamin D appears to be necessary for interferon-γ dependent T cell responses to infection. In low vitamin D states, dysfunctional macrophage activity becomes evident. Vitamin D is also an important link between Toll Like Receptor (TLR) activation and antibacterial response. Human macrophages stimulated by TLR induce: 1) vitamin D receptor expression; 2) conversion of 25(OH)D to its most biologically active form of 1,25-dihydroxyvitamin D; and 3) production of cathelicidin (LL-37), an endogenous antimicrobial peptide with potent activity against bacteria, viruses, fungi, and mycobacteria. LL-37 is highly expressed in both the plasma and at natural barrier sites (e.g. skin, gut, lungs) and may represent an important first-line of defense for the innate immune system.

In humans, cholecalciferol (vitamin D3) is either obtained through the diet or synthesized by skin upon exposure to ultraviolet B (UVB) radiation. Cholecalciferol is converted to 25(OH)D in the liver or by cells of the immune system. Serum 25(OH)D can be measured with relative ease and is the most abundant vitamin D metabolite. It is therefore, often used as a proxy for total body vitamin D status and 25(OH)D levels <30 ng/mL characterize an insufficient state. A growing body of evidence suggests that a significant proportion (50-90%) of critically ill patients may have insufficient 25(OH)D levels during admission to the intensive care unit (ICU). 25(OH)D insufficiency, in turn, appears to be associated with a higher risk of mortality in critically ill patients. However, randomized, placebo-controlled trials (RCTs) aimed at studying the effect of vitamin D supplementation in critical illness are limited and have largely focused on superficial assessments of vitamin D status. While it is known that septic patients have nearly universally low 25(OH)D levels and that the vitamin D levels are inversely correlated with the severity of sepsis, little is known regarding the effects of vitamin supplementation in this patient cohort. Therefore, our goal is to determine whether vitamin D supplementation in patients highly suspected of sepsis syndrome may be effective in optimizing 25(OH)D levels and in improving host production of the antimicrobial polypeptide LL-37.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • English or Spanish speaking
  • Within 24 hours of a suspected diagnosis of sepsis
  • Meeting criteria for sepsis (defined as suspected or confirmed infection AND at least one diagnostic criteria in each of the following groupings):

    1. Vital signs:

      1. Temperature: >38.3C or <36C
      2. HR: >90/min, or >2 standard deviation above normal
      3. Tachypnea (>20 breaths per minute)
      4. Altered mental status
      5. Positive fluid balance (>20 mL/Kg over 24 hrs)
      6. Glucose >140 mg/dL in the absence of diabetes mellitus
    2. Inflammatory markers:

      1. WBC: >12,000 or <4,000
      2. Normal WBC count with >10% immature forms
      3. CRP >2 standard deviation above normal value
      4. Pro‐ calcitonin >2 standard deviation above normal value
    3. Hemodynamic

      1. SBP <90mmHg, MAP <70mmHg or SBP decrease >40mmHg
      2. Vasopressor therapy to maintain MAP >65mmHg
    4. Organ dysfunction

      1. Arterial hypoxemia (PaO2/FiO2 <300)
      2. Acute Oliguria (UoP <0.5 mL/Kg/hr for at least 2 hours)
      3. Cr increase >0.5 mg/dL
      4. Coagulopathy: INR >1.5 or aPTT >60 sec
      5. Thrombocytopenia: PLT <100K
      6. Hyperbilirubinemia: TBili >4 mg/dL
    5. Tissue perfusion

      1. Lactate >2 mmol/L
      2. Decrease cap refill or mottling

Exclusion Criteria:

  • Pregnant females or immediate post-partum status
  • "Comfort measures only" status
  • Inability to provide informed consent or have a surrogate consent
  • History of renal stones within the past year
  • History of hypercalcemia within the past year
  • Baseline serum total calcium >10 mg/dL
  • Established diagnosis associated with increased risk of hypercalcemia (e.g. metastatic cancer, sarcoidosis, multiple myeloma, primary hyperparathyroidism)
  • History of severe anemia (Hematocrit <25%)
  • Medications that affect vitamin D metabolism (e.g. antiepileptics, tuberculosis medication
  • Already enrolled or planning to enroll in a research study that would conflict with full participation in the current study or confound the observation or interpretation of the study findings
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01896544

Contacts
Contact: Livnat Blum, BA 617-643-5430 lblum@partners.org
Contact: Caitlin McCarthy, BA 617-643-5430 cmccarthy22@partners.org

Locations
United States, Massachusetts
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02114
Sponsors and Collaborators
Massachusetts General Hospital
Investigators
Principal Investigator: Sadeq A Quraishi, MD, MHA, MMSc Harvard Medical School, Massachusetts General Hospital
  More Information

No publications provided

Responsible Party: Sadeq A. Quraishi, Assistant Professor of Anaesthesia, Harvard Medical School, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT01896544     History of Changes
Other Study ID Numbers: 2013P001406
Study First Received: July 8, 2013
Last Updated: February 23, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by Massachusetts General Hospital:
cholecalciferol
vitamin D
sepsis
infection

Additional relevant MeSH terms:
Rickets
Avitaminosis
Vitamin D Deficiency
Deficiency Diseases
Malnutrition
Nutrition Disorders
Bone Diseases, Metabolic
Bone Diseases
Musculoskeletal Diseases
Calcium Metabolism Disorders
Metabolic Diseases
Cholecalciferol
Vitamins
Micronutrients
Growth Substances
Physiological Effects of Drugs
Pharmacologic Actions
Bone Density Conservation Agents

ClinicalTrials.gov processed this record on October 19, 2014