Clinical Trials Register

Summary
EudraCT Number:	2010-023986-23
Sponsor's Protocol Code Number:	LF-0802
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2011-03-01
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Belgium - FPS Health-DGM

A.2

EudraCT number

2010-023986-23

A.3

Full title of the trial

OASIS: A Phase 2/3 Randomized, Double-blind, Placebo-controlled Study of the Safety and Efficacy of Talactoferrin Alfa in Patients with Severe Sepsis

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

OASIS: A Phase 2/3 Randomized, Double-blind, Placebo-controlled Study of the Safety and Efficacy of Talactoferrin Alfa in Patients with Severe Sepsis

A.3.2

Name or abbreviated title of the trial where available

OASIS

A.4.1

Sponsor's protocol code number

LF-0802

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01273779

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Agennix Incorporated
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Agennix AG
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Agennix Incorporated
B.5.2	Functional name of contact point	Clinical Trial Information Desk
B.5.3	Address:
B.5.3.1	Street Address	Eight Greenway Plaza, Suite 910
B.5.3.2	Town/ city	Houston
B.5.3.3	Post code	77046
B.5.3.4	Country	United States
B.5.4	Telephone number	+ 713-552-1091
B.5.5	Fax number	+ 713-552-0795
B.5.6	E-mail	clinicaltrialinfo@agennix.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Talactoferrin alfa
D.3.2	Product code	Talactoferrin Oral Solution (development name)
D.3.4	Pharmaceutical form	Oral solution
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Talactoferrinum alfa
D.3.9.1	CAS number	308240-58-6
D.3.9.2	Current sponsor code	Talactoferrin alfa
D.3.9.3	Other descriptive name	Talactoferrin, recombinant human lactoferrin, rhLF, TLF
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Oral solution
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Severe Sepsis

E.1.1.1

Medical condition in easily understood language

infection causing critical illness

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	14.0
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

E.1.3

Condition being studied is a rare disease

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.

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.

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.

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 infecting organism such as pneumococcal antigen or Legionella antigen, and
B.the presence of at least three manifestations of the 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, esophageal 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

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

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.

E.5.1.1

Timepoint(s) of evaluation of this end point

28 days (672 hours) from the first dose of study drug

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.

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

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

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

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

Yes

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

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

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

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

Spain

United Kingdom

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

Please refer to protocol

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1