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

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ClinicalTrials.gov Identifier: NCT04411472
Recruitment Status : Recruiting
First Posted : June 2, 2020
Last Update Posted : November 4, 2020
Sponsor:
Information provided by (Responsible Party):
AM-Pharma

Brief 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 COVID-19 population: Patients with proven or suspected SARS-CoV-2 at time of randomization with or without 'moderate' CKD.

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.


Condition or disease Intervention/treatment Phase
Acute Kidney Injury Due to Sepsis Biological: Recombinant human alkaline phosphatase Other: Placebo Phase 3

Detailed 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1600 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A DB, Placebo-Controlled, Two-Arm Parallel-Group, Phase 3 RCT to Investigate the Efficacy and Safety of Recombinant Human Alkaline Phosphatase for Treatment of Patients With SA-AKI
Actual Study Start Date : November 2, 2020
Estimated Primary Completion Date : August 15, 2023
Estimated Study Completion Date : February 15, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Sepsis

Arm Intervention/treatment
Experimental: active
recombinant human alkaline phosphatase 1.6mg/kg 3 daily 1 hour infusions
Biological: Recombinant human alkaline phosphatase
patients with SA-AKI are randomly assigned in a 1:1 ratio to either placebo or 1.6 mg/kg recAP.

Placebo Comparator: placebo
matching placebo
Other: Placebo
Placebo




Primary Outcome Measures :
  1. 28-day all-cause mortality [ Time Frame: 28 days ]
    To demonstrate an effect of recAP on 28 day all cause mortality


Secondary Outcome Measures :
  1. To investigate the effect of recAP on long-term Major Adverse Kidney Events (MAKE). [ Time Frame: 90 Days ]
    MAKE 90: dead or on RRT or ≥25% decline in estimated glomerular filtration rate (eGFR) on Day 90 relative to the known or assumed pre-AKI reference level.

  2. To investigate the effect of recAP on use of organ support, i.e., mechanical ventilation (MV), Renal Replacement Therapy (RRT), vasopressors or inotropes. [ Time Frame: 28 days ]
    Days alive and free of organ support through Day 28, i.e., days alive with no MV, RRT, vasopressors or inotropes (with death within 28 days counting as zero days).

  3. To investigate the effect of recAP on length of stay (LOS) in ICU. [ Time Frame: 28 days ]
    Days alive and out of the ICU through Day 28 (with death within 28 days counting as zero days).

  4. To investigate the effect of recAP on 90-day allcause mortality [ Time Frame: 90 days ]
    Time to death through Day 90.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. 18 years or older.
  2. In the ICU or intermediate care unit for clinical reasons.
  3. Have sepsis requiring vasopressor (norepinephrine, epinephrine, dopamine, phenylephrine, vasopressin, or angiotensin II) therapy, i.e.:

    1. suspected or proven bacterial or viral infection. and
    2. 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.

  4. Have AKI according to at least one of the below KDIGO criteria, a to d:

    1. An absolute increase in serum or plasma creatinine (CR) by ≥0.3 mg/dL (≥26.5 µmol/L) within 48 hours.

      or

    2. 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

    3. A decrease in urinary output to <0.5 mL/kg/hour for a minimum of 6 hours following adequate fluid resuscitation.

      or

    4. 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.
  5. Provision of signed and dated ICF in accordance with local regulations.

Exclusion Criteria:

  1. Documented CKD as specified below:

    1. At selected sites where enrolment of 'moderate' CKD patients is allowed:

      'Severe' CKD defined as a pre-AKI reference eGFR <25 mL/min/1.73 m2.

      • For patients with known CKD, the most recent eGFR prior to index hospitalization 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 'severe' CKD.
    2. At all other sites:

    'Moderate' and 'severe' CKD defined as a pre-AKI reference eGFR <45 mL/min/1.73 m2.

    • For patients with known CKD, the most recent eGFR prior to index hospitalization 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 'moderate' and 'severe' CKD.
  2. Advanced chronic liver disease, defined as a Child-Pugh score of 10 to 15 (Class C).
  3. Acute pancreatitis with no established source of infection.
  4. Urosepsis related to suspected or proven urinary tract obstruction.
  5. Main cause of AKI not sepsis.
  6. Proven or suspected SARS-CoV-2 infection. NOTE: This exclusion criterion does not apply to patients in the COVID-19 population.
  7. Severe burns requiring ICU treatment.
  8. Severely immunosuppressed, e.g. due to:

    • hematopoietic cell transplantation within past 6 months prior to Screening or acute or chronic graft-versus-host disease
    • solid organ transplantation
    • leukopenia not related to sepsis, i.e., preceding sepsis
    • Human Immunodeficiency Virus (HIV)/Acquired Immune Deficiency Syndrome (AIDS)
    • receiving chemotherapy within 30 days prior to Screening.
  9. 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.
  10. Limitations to use of mechanical ventilation (MV), RRT or vasopressors and inotropes (NOTE: limitation of cardiopulmonary resuscitation (CPR) only is not an exclusion criterion).
  11. Previous administration of recAP.
  12. 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).
  13. Current or planned extracorporeal membrane oxygenation (ECMO).
  14. On RRT >24 hours before start of trial drug.
  15. No longer on vasopressor therapy at time of randomization.
  16. On continuous vasopressor therapy for >72 hours before start of trial drug.
  17. 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.
  18. Not feasible to start trial drug within:

    1. 48 hours from AKI diagnosis, when AKI diagnosis precedes start of vasopressor therapy.

      or

    2. 24 hours from AKI diagnosis, when AKI is diagnosed after start of vasopressor therapy.
  19. Pregnant or nursing women.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04411472


Contacts
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Contact: Annelies Legters +31625300164 a.legters@am-pharma.com
Contact: Kristie Bass +31629334633 k.bass@am-pharma.com

Locations
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Netherlands
Jeroen Bosch Ziekenhuis lokatie GZG Recruiting
's-Hertogenbosch, Netherlands
Contact: F.W. Rozendaal, MD       W.Rozendaal@jbz.nl   
Principal Investigator: F.W. Rozendaal, MD         
Sponsors and Collaborators
AM-Pharma
Investigators
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Study Director: Annelies Legters AM-Pharma
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Responsible Party: AM-Pharma
ClinicalTrials.gov Identifier: NCT04411472    
Other Study ID Numbers: AP-recAP-AKI-03-01
First Posted: June 2, 2020    Key Record Dates
Last Update Posted: November 4, 2020
Last Verified: October 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Sepsis
Acute Kidney Injury
Infection
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes
Renal Insufficiency
Kidney Diseases
Urologic Diseases