Sepsis, Severe, Septic Shock
Conditions
Keywords
cholesterol, lipids, total parenteral nutrition
Brief summary
Briefly, this pilot clinical trial will evaluate preliminary safety and efficacy of the study drug (Smoflipid) at elevating cholesterol levels (primary outcome) in patients with sepsis and moderate organ dysfunction and will also evaluate measures of organ dysfunction, mortality, and biological activity (secondary outcomes).
Detailed description
Sepsis is a life-threatening disease for which there are no effective treatments. It results from metabolic and immunologic derangements that lead to organ dysfunction, shock and sometimes death. Both good (high density lipoprotein, HDL) and bad (low density lipoprotein, LDL) cholesterol should be protective against sepsis by helping to clear bacterial toxins from the blood stream and by providing a fuel for endogenous corticosteroids, part of the body's protective stress-response in shock. However, for partially unknown reasons, cholesterol levels drop to critically low levels in early sepsis, leaving the body unable to protect itself against sepsis via these mechanisms. Currently, lipid emulsions are available that are FDA approved for intravenous nutrition in critically ill patients (including sepsis) and may be capable of elevating serum cholesterol levels. This Phase II randomized pilot clinical trial, proposes to assess the following in a cohort of patients with early sepsis (first 24 hours): 1) safety and tolerability of the proposed lipid injectable emulsion (Smoflipid) and any adverse effects, 2) the drugs ability to optimally elevate cholesterol at 48 hours, and 3) preliminary measures of biological activity and clinical outcomes.
Interventions
DRUGSmoflipid
Administration of lipid injectable emulsion
Sponsors
University of Florida
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
Because this is a pilot study, and because the lipid emulsion appears white and was visible to the treatment team, the study was not blinded. Data abstractors were blinded to the treatment effect. As the treatment effects are objective measurements (lipid levels, SOFA score, etc.) the likelihood of bias is low.
Intervention model description
The study has a Phase I/II design. For the Phase I study, 10 patients were enrolled, and 9 completed the study. The Phase I study was designed to test the maximum tolerated dose of Smoflipid in escalating doses from 1.0 g/kg, 1.2 g/kg, 1.4 g/kg, and 1.6 g/kg. One patient withdrew from the study for social reasons. The Phase II trial was a randomized clinical trial to test the efficacy of 3 doses of study drug (1.2 g/kg, 1.4 g/kg, and 1.6 g/kg) for the primary outcome of cholesterol stabilization at 48 hours. 49 patients were enrolled and randomized. Two patients were withdrawn prior to drug. 47 patients completed the study protocol. Trial patients were randomized to receive either Smoflipid or control (no active treatment) using a Bayesian Optimal Interval Design. Thus, the Phase II arm included 24 patients in the control arm and 23 patients randomized to one of the three most efficacious doses of the study drug based on body weight, while the control group received no drug.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. age \> 18, 2. primary diagnosis of sepsis and within 24 hours of sepsis recognition and treated with institutional sepsis algorithm, 3. SOFA score ≥ 4, 4. screening total cholesterol ≤ 100 mg/dL or HDL-C + LDL-C ≤ 70 mg/dL
Exclusion criteria
1. total bilirubin \> 2 mg/dL, 2. serum albumin \< 1.5 mg/dL, 3. hypersensitivity to fish, egg, soybean, or peanut protein, or to any of the active ingredients or excipients, 4. severe hyperlipidemia or severe disorders of lipid metabolism with serum triglycerides \> 400 mg/dL, 5. alternative/confounding diagnosis causing shock or critical illness (e.g., myocardial infarction or pulmonary embolus, massive hemorrhage, trauma), 6. significant traumatic brain injury (evidence of neurologic injury on CT scan and a GCS \<8), 7. refractory shock (likely death within 12 hours), 8. established Do Not Resuscitate status or advanced directives restricting aggressive care or treating physician deems aggressive care unsuitable, 9. anticipated requirement for surgery that would interfere with drug infusion, 10. severe primary blood coagulation disorder, 11. acute pancreatitis accompanied by hyperlipidemia, 12. acute thromboembolic disease, 13. uncontrollable source of sepsis (e.g., irreversible disease state such as unresectable dead bowel), 14. severe immunocompromised state (e.g. subject has neutropenia receiving cytotoxic chemotherapy with absolute neutrophil count \< 500/ul or expected to decline to \< 500/uL within the next 3 days), 15. pregnancy or lactation 16. already receiving intravenous lipid formulations (e.g., TPN, propofol) will be excluded from the study as lipid infusion will interfere with interpretation of the study results. 17. Child Pugh Class B/C liver disease patients or liver transplant recipient 18. Patients on, or anticipated to be placed on, ECMO within 48 hours of enrollment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase II - Primary Outcome - Change in Total Cholesterol (48 Hours - Enrollment) | 48 hours | Change in total cholesterol (48 hour - enrollment value) of 0 to +5 mg/dL |
| Phase I - Primary Outcome - Maximum Tolerated Dose/Participants Experiencing Dose Related Toxicity | First 48 hours | Using sequential dose escalation, participants received 2 doses of 1.0 to 1.6 g/kg of lipid emulsion (Smoflipid 20% lipid emulsion) within 48 hours of enrollment to test the maximum tolerated dose of study drug. The maximum tolerated dose was defined by patients exhibiting specific dose-related toxicities from administration of escalating doses of the study drug. Of 9 patients, adverse events were only considered dose-limiting toxicities if they met the predefined study protocol criteria. None of these were classified as dose limiting or serious. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase II - Secondary Outcome - Organ Dysfunction | 48 hours | Sequential Organ Failure Assessment (SOFA) Score, this is a numerical score ranging from 0 to 24. A Higher SOFA score represents worsening organ dysfunction is correlated with higher rate of mortality. We measured the change over 48 hours. |
Countries
United States
Participant flow
Recruitment details
The study has a Phase II design. After evaluating for DLT, 49 enrolled (2 withdrawals) with 47 patients completing the Phase II study to either Smoflipid (intervention) or control. Only Phase II data are reported here.
Participants by arm
| Arm | Count |
|---|---|
| Phase II - 1.2 g/kg Smoflipid Infusion of drug (Smoflipid) will occur over a 16.5 hour period given once per day for the first two days of study enrollment.
Smoflipid: Administration of lipid injectable emulsion | 10 |
| Phase II - 1.4 g/kg Smoflipid Infusion of drug (Smoflipid) will occur over a 16.5 hour period given once per day for the first two days of study enrollment.
Smoflipid: Administration of lipid injectable emulsion | 4 |
| Phase II - 1.6 g/kg Smoflipid Infusion of drug (Smoflipid) will occur over a 16.5 hour period given once per day for the first two days of study enrollment.
Smoflipid: Administration of lipid injectable emulsion | 9 |
| Phase II - Control Patients will be followed as active controls, cholesterol levels and labs for lipid measures will be drawn. | 24 |
| Phase I - 1.0 g/kg Smoflipid Infusion of drug (Smoflipid) will occur over a 16.5 hour period given once per day for the first two days of study enrollment.
Smoflipid: Administration of lipid injectable emulsion | 2 |
| Phase I - 1.2 g/kg Smoflipid Infusion of drug (Smoflipid) will occur over a 16.5 hour period given once per day for the first two days of study enrollment.
Smoflipid: Administration of lipid injectable emulsion | 2 |
| Phase I - 1.4 g/kg Smoflipid Infusion of drug (Smoflipid) will occur over a 16.5 hour period given once per day for the first two days of study enrollment.
Smoflipid: Administration of lipid injectable emulsion | 2 |
| Phase I - 1.6 g/kg Smoflipid Infusion of drug (Smoflipid) will occur over a 16.5 hour period given once per day for the first two days of study enrollment.
Smoflipid: Administration of lipid injectable emulsion | 3 |
| Total | 56 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Withdrawal | 1 | 0 | 1 | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Phase II - 1.2 g/kg Smoflipid | Total | Phase I - 1.6 g/kg Smoflipid | Phase I - 1.4 g/kg Smoflipid | Phase I - 1.2 g/kg Smoflipid | Phase I - 1.0 g/kg Smoflipid | Phase II - Control | Phase II - 1.6 g/kg Smoflipid | Phase II - 1.4 g/kg Smoflipid |
|---|---|---|---|---|---|---|---|---|---|
| Age, Customized Age, y | 71 years | 65 years | 59 years | 53 years | 53 years | 66 years | 68 years | 67 years | 63 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 26 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 11 Participants | 5 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 5 Participants | 28 Participants | 2 Participants | 2 Participants | 1 Participants | 1 Participants | 12 Participants | 4 Participants | 1 Participants |
| Region of Enrollment United States | 10 participants | 56 participants | 3 participants | 2 participants | 2 participants | 2 participants | 24 participants | 9 participants | 4 participants |
| Sex: Female, Male Female | 8 Participants | 24 Participants | 2 Participants | 1 Participants | 0 Participants | 1 Participants | 10 Participants | 2 Participants | 0 Participants |
| Sex: Female, Male Male | 2 Participants | 32 Participants | 1 Participants | 1 Participants | 2 Participants | 1 Participants | 14 Participants | 7 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 10 | 3 / 4 | 0 / 9 | 7 / 24 | 1 / 2 | 0 / 2 | 0 / 2 | 2 / 3 |
| other Total, other adverse events | 6 / 10 | 3 / 4 | 7 / 9 | 8 / 24 | 2 / 2 | 1 / 2 | 2 / 2 | 2 / 3 |
| serious Total, serious adverse events | 2 / 10 | 3 / 4 | 1 / 9 | 8 / 24 | 2 / 2 | 0 / 2 | 0 / 2 | 2 / 3 |
Outcome results
Primary
Phase II - Primary Outcome - Change in Total Cholesterol (48 Hours - Enrollment)
Change in total cholesterol (48 hour - enrollment value) of 0 to +5 mg/dL
Time frame: 48 hours
Population: Phase II participants were analyzed for the primary outcome of change in total cholesterol at 48 hours (47 patients) at doses of 1.2, 1.4 and 1.6 g/kg. Phase I participants were also analyzed for this outcome, although it was not the primary outcome for this phase (which was maximum tolerated dose).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase II - 1.2 g/kg Smoflipid | Phase II - Primary Outcome - Change in Total Cholesterol (48 Hours - Enrollment) | 9 mg/dL | Standard Deviation 17 |
| Phase II - 1.4 g/kg Smoflipid | Phase II - Primary Outcome - Change in Total Cholesterol (48 Hours - Enrollment) | -10 mg/dL | Standard Deviation 29 |
| Phase II - 1.6 g/kg Smoflipid | Phase II - Primary Outcome - Change in Total Cholesterol (48 Hours - Enrollment) | 4 mg/dL | Standard Deviation 21 |
| Phase II - Control | Phase II - Primary Outcome - Change in Total Cholesterol (48 Hours - Enrollment) | 2 mg/dL | Standard Deviation 18 |
| Phase I - 1.0 g/kg Smoflipid | Phase II - Primary Outcome - Change in Total Cholesterol (48 Hours - Enrollment) | -12 mg/dL | Standard Deviation 23 |
| Phase I - 1.2 g/kg Smoflipid | Phase II - Primary Outcome - Change in Total Cholesterol (48 Hours - Enrollment) | 16 mg/dL | Standard Deviation 1 |
| Phase I - 1.4 g/kg Smoflipid | Phase II - Primary Outcome - Change in Total Cholesterol (48 Hours - Enrollment) | -9 mg/dL | Standard Deviation 10 |
| Phase I - 1.6 g/kg Smoflipid | Phase II - Primary Outcome - Change in Total Cholesterol (48 Hours - Enrollment) | -18 mg/dL | Standard Deviation 9 |
Primary
Phase I - Primary Outcome - Maximum Tolerated Dose/Participants Experiencing Dose Related Toxicity
Using sequential dose escalation, participants received 2 doses of 1.0 to 1.6 g/kg of lipid emulsion (Smoflipid 20% lipid emulsion) within 48 hours of enrollment to test the maximum tolerated dose of study drug. The maximum tolerated dose was defined by patients exhibiting specific dose-related toxicities from administration of escalating doses of the study drug. Of 9 patients, adverse events were only considered dose-limiting toxicities if they met the predefined study protocol criteria. None of these were classified as dose limiting or serious.
Time frame: First 48 hours
Population: Only Phase I trial patients were analyzed for this component of the study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase II - 1.2 g/kg Smoflipid | Phase I - Primary Outcome - Maximum Tolerated Dose/Participants Experiencing Dose Related Toxicity | 0 Participants |
| Phase II - 1.4 g/kg Smoflipid | Phase I - Primary Outcome - Maximum Tolerated Dose/Participants Experiencing Dose Related Toxicity | 0 Participants |
| Phase II - 1.6 g/kg Smoflipid | Phase I - Primary Outcome - Maximum Tolerated Dose/Participants Experiencing Dose Related Toxicity | 0 Participants |
| Phase II - Control | Phase I - Primary Outcome - Maximum Tolerated Dose/Participants Experiencing Dose Related Toxicity | 0 Participants |
| Phase I - 1.0 g/kg Smoflipid | Phase I - Primary Outcome - Maximum Tolerated Dose/Participants Experiencing Dose Related Toxicity | 0 Participants |
| Phase I - 1.2 g/kg Smoflipid | Phase I - Primary Outcome - Maximum Tolerated Dose/Participants Experiencing Dose Related Toxicity | 0 Participants |
| Phase I - 1.4 g/kg Smoflipid | Phase I - Primary Outcome - Maximum Tolerated Dose/Participants Experiencing Dose Related Toxicity | 0 Participants |
| Phase I - 1.6 g/kg Smoflipid | Phase I - Primary Outcome - Maximum Tolerated Dose/Participants Experiencing Dose Related Toxicity | 0 Participants |
Comparison: Using sequential dose escalation, participants received 2 doses of 1.0 to 1.6 g/kg of lipid emulsion (Smoflipid 20% lipid emulsion) within 48 hours of enrollment to test the maximum tolerated dose of study drug. The maximum tolerated dose was defined by patients exhibiting specific dose-related toxicities from administration of escalating doses of the study drug. Of 9 patients, adverse events were only considered dose-limiting toxicities if they met the predefined study protocol criteria.
Secondary
Phase II - Secondary Outcome - Organ Dysfunction
Sequential Organ Failure Assessment (SOFA) Score, this is a numerical score ranging from 0 to 24. A Higher SOFA score represents worsening organ dysfunction is correlated with higher rate of mortality. We measured the change over 48 hours.
Time frame: 48 hours
Population: Phase I and II participants were analyzed for this secondary outcome of change in SOFA score from 0 to 48 hours.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase II - 1.2 g/kg Smoflipid | Phase II - Secondary Outcome - Organ Dysfunction | 1 score on a scale |
| Phase II - 1.4 g/kg Smoflipid | Phase II - Secondary Outcome - Organ Dysfunction | 0 score on a scale |
| Phase II - 1.6 g/kg Smoflipid | Phase II - Secondary Outcome - Organ Dysfunction | -2 score on a scale |
| Phase II - Control | Phase II - Secondary Outcome - Organ Dysfunction | -2 score on a scale |
| Phase I - 1.0 g/kg Smoflipid | Phase II - Secondary Outcome - Organ Dysfunction | 4 score on a scale |
| Phase I - 1.2 g/kg Smoflipid | Phase II - Secondary Outcome - Organ Dysfunction | -5 score on a scale |
| Phase I - 1.4 g/kg Smoflipid | Phase II - Secondary Outcome - Organ Dysfunction | -2 score on a scale |
| Phase I - 1.6 g/kg Smoflipid | Phase II - Secondary Outcome - Organ Dysfunction | 0 score on a scale |