E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
infection causing critical illness |
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E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10040047 |
E.1.2 | Term | Sepsis |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective is to determine the effect of oral talactoferrin alfa on 28-day (672-hour post first dose of study drug) all-cause mortality in patients with severe sepsis. |
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E.2.2 | Secondary objectives of the trial |
The secondary efficacy objectives are to determine the effect of oral talactoferrin alfa on:
•3-month all-cause mortality
•6-month all-cause mortality
•12-month all-cause mortality
•Overall survival
•Number of 28-day intensive-care-unit (ICU) free days
•Number of 28-day shock-free days
•Number of 28-day ventilator-free days
•Number of 28-day dialysis-free days
•Number of 28-day organ dysfunction-free days
•Incidence and severity of additional sepsis-related organ dysfunction
•Incidence of new infections, relapses, and superinfections
•Time to initial ICU discharge from first dose of study drug
•Duration of hospitalization from first dose of study drug
The secondary safety objective is to assess safety and tolerabiliity of oral talactoferrin alfa in patients with severe sepsis.
An additional secondary objective is to assess pharmacoeconomic and quality of life parameters.
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Protocol Title: LF-0802A: A Pharmacokinetic, Pharmacodynamic and Echocardiographic Sub-Study of Talactoferrin Alfa in Patients with Severe Sepsis Who are Participating in Protocol LF-0802
Version 1.0, date 17 January 2011.
Objective: The primary objective of the study is to evaluate the PK/PD parameters of oral TLF in patients with severe sepsis. Patients will provide a separate consent for this study and will be able to opt out.
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E.3 | Principal inclusion criteria |
1.Age 18 years
2.Onset of severe sepsis within the previous 24 hours as defined by meeting all of the following criteria (A, B and C). Organ dysfunction must be present at the time of randomization. Randomization must occur within 24 hours of the first documented organ dysfunction (C) as defined below (refer to Appendix F for the definitions of start time for each type of organ dysfunction):
A.Objective evidence of confirmed or suspected infection. Suspected infection must be based on objective clinical evidence such as: (a) neutrophils in a normally sterile body fluid; (b) perforated viscus; (c) radiographic evidence of pneumonia; or (d) a syndrome associated with a high likelihood of infection (e.g., ascending cholangitis), (e) evidence of an infection organism such as pneumococcal antigen or Legionella antigen, and
B.the presence of at least three manifestations of a systemic inflammatory response syndrome (SIRS) due to infection (only two criteria if patient is on medication that controls heart rate or has a pacemaker) within 24 hours prior to start time of the first qualifying organ dysfunction or within 24 hours after the start time of the first qualifying organ dysfunction (see Inclusion Criterion 2C),:
•Body temperature: i) hyperthermia as indicated by a temperature of ≥38º C (100.4º F); or ii) hypothermia as indicated by a core temperature ≤36º C (96.8º F). For defining hypothermia, temperature must be obtained via a rectal temperature, central venous catheter monitor, esoohageal thermistor, or urinary bladder thermistor, not by oral, tympanic or axillary measurement.
•Heart rate ≥90/min
•Respiratory rate ≥20/min or PaCO2 ≤ 32 mmHg; or the use of mechanical ventilation for an acute respiratory process
•WBC ≥12,000/mm3 or ≤4,000/mm3, or >10% immature neutrophils (i.e., bands) [Note: In the presence of granulocyte colony stimulating factor, for those patients whose WBC is > 12000 cells/mm3, the patient must have hyperthermia and at least one other criterion (HR or RR)]
and
C.at least one acute organ dysfunction due to sepsis, that is newly developed, and not explained by other disease processes or the effects of treatment and is ongoing at the time of randomization, defined as follows:
•Septic shock (Cardiovascular) – the requirement for vasopressors,* despite adequate fluid resuscitation,** to maintain a MAP >65 mm Hg or a systolic pressure >90 mm Hg. (Note: for patients who develop cardiovascular dysfunction in the setting of intubation, this dysfunction must persist for ≥ 1 hour post intubation).
* Vasopressors are defined as dopamine ≥5 µg/kg/min or any dose of norepinephrine, epinephrine, phenylephrine, or vasopressin, with the intent to support blood pressure. Dobutamine and dopexamine are not considered vasopressors.
**Adequate fluid resuscitation is defined as one of the following: i) a minimum of a 20 mL/kg (ideal body weight) intravenous fluid challenge (crystalloid or equivalent colloid); 10 mL/kg of colloids = 20
mL/kg crystalloids) within a 6 hour period or a minimum of 30mL/kg
crystalloid or equivalent colloid within 24 hours)
or ii) if measured, a central venous pressure (CVP) ≥8 mm Hg or ≥12 mm Hg if mechanically ventilated; or iii) a pulmonary artery occlusion pressure (PAOP) ≥12 mm Hg or ≥16 mm Hg if mechanically ventilated.
•Respiratory – must have mechanical ventilation and PaO2/FiO2 ratio ≤300 (SpO2/FiO2 ≤357) or if lung is the primary site of infection a PaO2/FiO2 ratio ≤200 (SpO2/FiO2 ≤214). Note: SpO2 may only be used if <97. Patient must not have received mechanical ventilation > 48
hours prior to randomization to qualify for respiratory organ dysfunction
(patient may qualify by meeting
another organ dysfunction).
•Renal – i) an absolute increase in serum creatinine of ≥0.3 mg/dL within the preceding 48 hours, or ii) a relative increase in serum creatinine ≥50% within the preceding 48 hours, or iii) a urine output<0.5 mL/kg ideal body weight/hr for ≥2 hours in the absence of known or suspected urinary tract obstruction. In the presence of pre-existing impairment of renal function (defined as a serum creatinine concentration >2 times the upper limit of the normal reference range prior to the onset of sepsis), the patient should meet another organ dysfunction criteria. Meeting criteria i) or ii) requires ≥2 creatinine measurements within 48 hours. Criteria i), ii) or iii) must be met despite adequate fluid resuscitation.** (defined as above for septic shock)
•Hematologic – platelet count <80,000/mm3 or platelet count <120,000/mm3 in association with a PT INR ≥1.2
•Metabolic – lactate > 4.0 mmol/L (or equivalent in other units) despite adequate fluid resuscitation** (defined as above for septic shock). If
metabolic organ dysfunction is the only qualifying organ dysfunction, a
qualifying lactate value must be obtained within 6 hours prior to
randomization.
3.Must be receiving antimicrobial therapy
INCLUSION CRITERIA 4-5 _ SEE PROTOCOL |
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E.4 | Principal exclusion criteria |
1.Enrollment in an interventional experimental protocol involving an
investigational drug or a medical device within 60 days prior to
randomization or within 5 half-lives of the study drug, whichever is
longer. Co-enrollment in process of care trials or comparative trials of
approved products will be allowed if the protocol has been approved in
advance by the sponsor, as long as the co-enrollment does not violate
participation in the other protocol.
2.Severe congestive heart failure (e.g., NYHA Class IV or most recent known pre-sepsis ejection fraction <30%)
3.Neutrophils <1,000/mm3 unless due to sepsis
4.Known HIV infection with CD4 <200 cells/mm3 or illnesses associated with end stage AIDS (e.g., disseminated Mycobacterium Avium Complex, Cytomegalovirus and Progressive Multifocal Leukoencephalopathy)
5.Presence of 3rd-degree burns involving >20% body surface area (unless burn occurred >7 days prior to randomization)
6.Receiving significant immunosuppressants,(see Appendix G, contact
Clinical Coordinating Center for advice) or significant steroid dose (e.g.,
>20 mg prednisone or a steroid with equivalent activity), daily for >2 weeks immediately prior to randomization.
7.Patient is moribund and whose death is considered imminent by the investigator
8.Life expectancy, due to pre-existing conditions such as cancer, is less than six months
9.Severe hypoxic encephalopathy (e.g., post cardiopulmonary resuscitation) or persistent vegetative state
10.Child-Pugh Class C liver disease pre-sepsis or known portal hypertension or esophageal varices
11.The patient or their legal representative, or the patient’s physician are not committed to providing full, aggressive, life support,[a "no CPR
(chest compressions) in the setting of cardiac arrest" order is allowed]
12.Patients chronically bed-bound prior to the onset of sepsis
13.Pregnant or breast-feeding
14. Receiving polymyxin B hemoperfusion or planned use of polymyxin B
hemoperfusion during the study
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint, 28-day all cause mortality rate is defined as the proportion of patients who die in the first 28 days (672 hours) from the
first dose of study drug. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
28 days (672 hours) from the first dose of study drug |
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E.5.2 | Secondary end point(s) |
It is anticipated that the dropout rate (and therefore missing data) will
increase with longer term follow-up; the 12-month dropout rate could be
as high to 25%. The statistical methods used for 3, 6, and 12-month
analyses will be the same as for the primary endpoint. Details on
imputation steps and methods for handling missing data will be included
in the Statistical Analysis Plan (SAP). Details on sensitivity analyses
performed for the 28-day mortality endpoint will also be included in the
SAP.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
3, 6, and 12 months from the date of first dose of study drug |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 120 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Belgium |
Canada |
Denmark |
France |
Germany |
Israel |
Netherlands |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |