The objectives of the study are to: -To evaluate the safety and tolerability of MOTREM in patients with septic shock. -To evaluate the effects of MOTREM exposure over up to 5 days in patients with septic shock -To evaluate the PK/PD and dose/PD…
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
Intensive care - septic shock
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety and tolerability parameters:
1. Vital signs: systolic (SBP) and diastolic (DBP) blood pressure, heart rate,
and body temperature (tympanic)
2. ECG (12-lead ECG)
3. Safety laboratory tests: haematology, coagulation, plasma biochemistry
4. Presence of anti-LR12 antibodies
5. Adverse events : from screening until study completion
Secondary outcome
Pharmacokinetics:
Plasma concentrations of LR12 will be measured by a validated LCMS/MS assay and
analysed using non-compartmental methods to obtain
estimates of the PK parameters.
Pharmacodynamics (exploratory)
The concentration profiles of biomarkers (sTREM-1, immune and vascular related
biomarkers) over time and biomarker mRNA levels will
be analysed.
Clinical parameters (exploratory)
1. Resolution of organ dysfunction (SOFA score total and individual domains)
2. Vasopressor use
3. Invasive mechanical ventilation
4. Renal support
5. Time until shock reversal defined as cessation of vasopressor support for 24
hours
6. Mortality at day 28 and Day 90
Background summary
Sepsis is an inflammation of the body secondary to an acute infection which can
be life-threatening. Sepsis occurs when chemicals released into the bloodstream
to fight the infection trigger defense responses throughout the body. Anyone
can develop sepsis, but the risk is higher in older adults or those with
weakened immune systems. If sepsis progresses to septic shock, blood pressure
drops dramatically with multiple organ consequences and an increased mortality.
An uncontrolled and overwhelming immune response is thought to be contributing
to high number of deaths in patients with septic shock. Sepsis and septic shock
is the most frequent cause of death in intensive care units (ICUs) and is the
11th leading cause of death worldwide. To date, people with sepsis are treated
with antibiotics to kill the bacteria responsible for the infection and other
general medications and procedures based on symptoms but no specific therapy is
currently available for septic shock.
MOTREM is an investigational new drug which has been developed by a
pharmaceutical company called INOTREM SA (the Sponsor). MOTREM is a chemically
synthesised peptide (small protein) that prevents amplification of the immune
response that can lead to the start and progression of sepsis into septic
shock. It inhibits activation of TREM-1 (a protein expressed on certain
circulating white blood cells). MOTREM has the potential to reverse
sepsis-related over-inflammation. Previous non-clinical studies showed that
MOTREM is able to control the immune system and to diminish the damage linked
to septic shock
Study objective
The objectives of the study are to:
-To evaluate the safety and tolerability of MOTREM in patients with
septic shock.
-To evaluate the effects of MOTREM exposure over up to 5 days in patients
with septic shock
-To evaluate the PK/PD and dose/PD relationship to TREM-1 pathway related
markers
-To evaluate the effect of MOTREM on transcriptomics
-To evaluate the effect of MOTREM on clinical parameters (e.g.
vasopressor doses, vasopressor-free days, ventilator-free days, mortality)
Study design
This is a randomised, double-blind, two-stage, placebo controlled study. It
consists of 2 stages with a similar treatment regimen, in which 0.3, 1.0 or 3.0
mg/kg/h of MOTREM is tested versus placebo.
After screening for eligibility, patients will be randomised to one of the
treatment arms. They will then either receive a 5 mg/kg loading dose of MOTREM
over 15 minutes followed by a continuous i.v. infusion of MOTREM or a matching
placebo on top of standard of care.
Treatment with study drug must be initiated as early as possible, but no later
than 24 hours after the onset of septic shock, defined by the start of
vasopressor therapy. Blood samples for the determination of MOTREM (LR12)
plasma concentrations and exploratory pharmacodynamic analyses will be
collected before and throughout the treatment period.
Patients will be treated until 12 (±2) hours after the resolution of their
septic shock (defined as vasopressor withdrawal) with a maximum treatment
duration of 5 days (120 hours).The survival status of patients after 28 and 90
days will be collected.
Stage 1 investigates multiple ascending doses of MOTREM or placebo in a
sequential design in cohorts of 4 patients (3:1 randomisation). After
completion of a cohort (for up to 5 days of infusion), safety and PK data will
be reviewed by an independent data safety monitoring board (DSMB) and the study
will progress to the next cohort/stage.
Stage 2 investigates 3 doses of MOTREM in a randomised, balanced,
parallel-group design involving up to 3 doses of MOTREM and a placebo arm. Only
dose arms of MOTREM considered to be safe and well tolerated during Stage 1
will be administered in Stage 2.
Intervention
Stage 1 is investigating multiple ascending doses of MOTREM or placebo in a
sequential design in cohorts of 4 patients (3:1 randomisation).
Stage 2 investigates 3 doses of MOTREM in a randomised, balanced,
parallel-group design involving up to 3 doses of MOTREM and a placebo arm.
Study burden and risks
There are no known side effects of MOTREM treatment.
To date, MOTREM has been administered to 27 healthy people (volunteers) MOTREM
in a previous research trial. MOTREM was considered safe and well tolerated up
to the highest dose tested. All reported adverse events in that study were mild
and considered unrelated to study drug. Based on non-clinical studies and the
clinical study in healthy volunteers it is expected that MOTREM will be safe
and well tolerated.
However, side effects of MOTREM treatment may occur. MOTREM has not been given
to septic shock patients prior to this study and one of the reasons for this
study is to learn more about the possible side effects of MOTREM. There may be
risks that we cannot predict, or rare or unknown side effects that could occur.
This study is conducted in hospitals experienced in the treatment of patients
with septic shock and with close medical supervision of patients. The potential
risks associated with the participation in this research trial will be
explained to subjects (or the legally authorised representative) before the
decision to participate or not. The medical and nursing staff will follow the
subject's condition closely from the onset of septic shock and look for as well
as treat any possible adverse event.
Other risks of taking part in this trial:
Sometimes people may experience rare sensitivity/allergic reactions to
medications. A sensitivity/ allergic reaction may include: itching; rash;
hives; difficulty breathing; tightness in the chest; swelling of your face,
lips, mouth, or tongue; wheezing. However, no allergic reactions to MOTREM
occurred in any prior trial.
The subject may experience some temporary discomfort, bruising, or rarely,
infection at the site of a needle stick, in the process of drawing blood
samples or inserting a catheter into your vein.
MOTREM is a peptide (small protein) which means that the body can potentially
recognise it as a foreign body and form antibodies to it. The possibility that
the subject reacts against MOTREM is very low since this experimental drug is
derived from a normal protein of the body. However, this possibility still
exists. Blood samples will be collected throughout the study to assess the
development of MOTREM antibodies (immunogenicity tests). Should the subject
develop anti-drug-antibodies, he/she will be followed up for at least 3 months
or until the antibody response is no longer detected and any adverse effect
linked to this reaction will be treated.
Rue de la Boétie 114
Paris 75008
FR
Rue de la Boétie 114
Paris 75008
FR
Listed location countries
Age
Inclusion criteria
1. Provide written informed consent (proxy/legal representative/independent physician/emergency consent) according to local regulations
2. Age 18* to 80 years
* 16 to 80 years in the Netherlands
Sepsis
3. Documented or suspected infection: lung, abdominal or elderly UTI (*65 years)
4. Organ dysfunction defined as acute change in SOFA score * 2 points
Shock
5. Refractory hypotension requiring vasopressors to maintain MAP *65mm Hg despite adequate volume resuscitation of at least 20 ml/kg within 6 hours (according to Surviving Sepsis guidelines, see Appendix 1)
6. Hyperlactatemia (blood lactate >2 mmol/l or 18 mg/dl). This criterion must be met at least once for the purpose of diagnosis within the 24 hours before study drug administration
Exclusion criteria
1. Previous episode of septic shock (vasopressor administration) within current hospital stay
2. Underlying concurrent immunodepression (specified in appendix 2)
3. Solid organ transplant requiring immunosuppressive therapy
4. Known pregnancy (positive serum pregnancy test)
5. Prolonged QT syndrome (QTc * 440 ms)
6. Shock of any other cause, e.g. hypotension related to gastrointestinal bleeding
7. Ongoing documented or suspected endocarditis, history of prosthetic heart valves
8. End-stage neurological disease
9. End-stage cirrhosis (Child Pugh Class C)
10. Acute Physiology And Chronic Health Evaluation (APACHE) II score * 34
11. End stage chronic renal disease requiring chronic dialysis
12. Home oxygen therapy on a regular basis for > 6 h/day
13. Severe obesity (BMI * 40)
14. Recent CPR (within current hospital stay)
15. Moribund patients
16. Decision to limit full care taken before obtaining informed consent
17. Participation in another interventional study in the 3 months prior to randomisation
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2016-005032-14-NL |
| CCMO | NL61182.091.17 |