(Revival) Study to Investigate the Efficacy and Safety of Alkaline Phosphatase in Patients With Sepsis-Associated AKI

  • STATUS
    Recruiting
  • End date
    Feb 15, 2024
  • participants needed
    1600
  • sponsor
    AM-Pharma
Updated on 20 June 2022

Summary

Clinical phase 3 study to investigate the effect of recAP on 28 day mortality in patients admitted to the ICU with acute kidney injury that is caused by sepsis.

The study has three distinct SA-AKI trial populations:

  1. The main trial population: Patients with a pre-AKI reference eGFR ≥45 mL/min/1.73 m2 and no proven or suspected SARS-CoV-2 at time of randomization.
  2. A 'moderate' CKD population: Patients with a pre-AKI reference eGFR ≥25 and <45 mL/min/1.73 m2 and no proven or suspected SARS-CoV-2 at time of randomization.
  3. A Corona Virus Disease 2019 (COVID-19) population: Patients with proven or suspected SARS-CoV-2 at time of randomization with or without 'moderate' CKD. For patients in this population, COVID-19 should be the main cause of SA-AKI.

In the main study population approximately 1400 patients will be enrolled and in the two cohorts with moderate CKD and COVID-19 each up to 100 patients.

There are two arms in the study, one with active treatment and one with an inactive compound (placebo). Treatment is by 1 hour intravenous infusion, for three days. Patients are followed up for 28 days to see if there is an improvement on mortality, and followed for 90 and 180 days for mortality and other outcomes e.g. long-term kidney function and quality of life.

Description

Sepsis is the leading cause of acute kidney injury (AKI) and a major cause of death. Patients with SA-AKI have a high mortality and morbidity and are at risk of developing chronic kidney disease. AP is a homodimeric endogenous enzyme present in many cells and organs, e.g., intestines, placenta, liver, bone, kidney, and granulocytes. It exerts detoxifying effects through dephosphorylation of endotoxins; pathogen associated molecular pattern molecules (PAMPS e.g., lipopolysaccharide) and damage-associated molecular pattern molecules (DAMPS e.g., adenosine tri- and di-phosphate). In animal models of sepsis and AKI, administration of AP attenuates the inflammatory response, improves renal function and/or reduces mortality.

AM-Pharma B.V. is developing AP as a novel, recombinant chimeric human AP medicinal product, called recAP, to be used as an intravenous infusion for the treatment of SA-AKI. In the Phase 2 trial STOP-AKI, a survival benefit was observed in the two highest dose groups, 0.8 mg/kg and 1.6 mg/kg groups, compared to the placebo group. There were no safety or tolerability concerns for any of the doses tested (0.4, 0.8 and 1.6 mg/kg). The 1.6 mg/kg recAP dose was selected for this Phase 3 trial based on the significant survival benefit observed. PK/PD simulations also confirmed this dose to have the most pronounced treatment effect.

The primary objective of this Phase 3 trial is to confirm the mortality benefit seen in STOP-AKI by demonstrating a reduction in 28 day all cause mortality in patients with SA-AKI treated with 1.6 mg/kg recAP.

Details
Condition Acute Kidney Injury Due to Sepsis
Treatment Placebo, Recombinant human alkaline phosphatase
Clinical Study IdentifierNCT04411472
SponsorAM-Pharma
Last Modified on20 June 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

18 years or older
In the ICU or intermediate care unit for clinical reasons
Have sepsis requiring vasopressor (norepinephrine, epinephrine, dopamine, phenylephrine, vasopressin, or angiotensin II) therapy, i.e
suspected or proven bacterial or viral infection. and
on vasopressor therapy (≥0.1 µg/kg/min norepinephrine or equivalent) for sepsis-induced hypotension for at least one hour despite adequate fluid resuscitation according to clinical judgement. Following the initial one hour on at least 0.1 µg/kg/min norepinephrine or equivalent, any dose of vasopressor counts as vasopressor therapy
The combination of a) and b) automatically ensures that patients fulfill the Sepsis 3
criteria as 0.1 µg/kg/min norepinephrine corresponds to a score of +4 on the
Cardiovascular sub-score of the SOFA score
Have AKI according to at least one of the below KDIGO criteria, a to d
An absolute increase in serum or plasma creatinine (CR) by ≥0.3 mg/dL (≥26.5
µmol/L) within 48 hours
or
A relative increase in CR to ≥1.5 times the pre-AKI reference CR value which is
known or presumed to have occurred within prior 7 days
or
following adequate fluid resuscitation
A decrease in urinary output to <0.5 mL/kg/hour for a minimum of 6 hours
or d) If the patient does not have a known history of CKD and there is no pre-AKI
reference CR value available from the past 12 months available from the past 12
months: a CR value greater or equal to the levels presented in Table 1, with the
increase in CR presumed to have occurred within prior 7 days
Provision of signed and dated ICF in accordance with local regulations

Exclusion Criteria

a) At sites where enrolment of 'moderate' CKD patients is allowed, patients with
'severe' CKD defined as a pre-AKI reference eGFR <25 mL/min/1.73 m2 are excluded
needs to be documented as ≥25 mL/min/1.73 m2
For patients with known CKD but no known eGFR prior to hospitalization
presentation eGFR between 25-60 mL/min/1.73 m2 can also be used to rule out
b) At sites where enrolment of 'moderate' CKD patients is NOT allowed, patients
'severe' CKD
with 'moderate' and 'severe' CKD defined as a pre-AKI reference eGFR <45
mL/min/1.73 m2 are excluded
solid organ transplantation
For patients with known CKD, the most recent eGFR prior to index hospitalization
leukopenia not related to sepsis, i.e., preceding sepsis
For patients with known CKD, the most recent eGFR prior to index hospitalization
Human Immunodeficiency Virus (HIV)/Acquired Immune Deficiency Syndrome (AIDS)
needs to be documented as ≥45 mL/min/1.73 m2
For patients with known CKD but no known eGFR prior to hospitalization
presentation eGFR between 45-60 mL/min/1.73 m2 can also be used to rule out
or
'moderate' and 'severe' CKD
Advanced chronic liver disease, defined as a Child-Pugh score of 10 to 15 (Class C)
Acute pancreatitis without proven infection
Urosepsis related to suspected or proven urinary tract obstruction
Main cause of AKI not sepsis
Proven or suspected SARS-CoV-2 infection. NOTE: This exclusion criterion does not
apply to patients in the COVID-19 population, in which COVID-19 should be the main
cause of SA-AKI
Severe burns requiring ICU treatment
Severely immunosuppressed, e.g. due to
hematopoietic cell transplantation within past 6 months prior to Screening or
acute or chronic graft-versus-host disease
receiving chemotherapy within 30 days prior to Screening
At high risk of being LTFU, e.g., due to known current or recent (within the last 6
months) IV drug abuse or known to be homeless
Limitations to use of mechanical ventilation (MV), RRT or vasopressors and inotropes
(NOTE: limitation of cardiopulmonary resuscitation (CPR) only is not an exclusion
criterion)
Previous administration of recAP
Use of a non-marketed drug within the last month or concurrent or planned
participation in a clinical trial for a non-marketed drug or device. (NOTE
Co-enrollment or concurrent participation in observational, non-interventional trials
using no protocolized treatments or procedures are always allowed. Co-enrollment or
concurrent participation in trials using protocolized treatments or procedures, e.g
blood draws, requires pre-approval by the TSC)
Current or planned extracorporeal membrane oxygenation (ECMO)
On RRT >24 hours before start of trial drug
No longer on vasopressor therapy at time of randomization
On continuous vasopressor therapy for >72 hours before start of trial drug
Estimated glomerular filtration rate (eGFR) >60 mL/min/1.73 m2 based on the most
recent available CR sample at time of screening (NOTE: will often be the sample used
to diagnose AKI). eGFR should be calculated using the Chronic Kidney Disease
Epidemiology Collaboration (CKD-EPI) formula. In Japan, the CKD-EPI formula with
Not feasible to start trial drug within
Japanese coefficient should be used. If local regulations prohibit correcting for race
48 hours from AKI diagnosis, when AKI diagnosis precedes start of vasopressor
in the calculation of eGFR, it is acceptable to use the formula without correcting for
therapy
race
24 hours from AKI diagnosis, when AKI is diagnosed after start of vasopressor
therapy
Pregnant or nursing women
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