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A Safety, Tolerability, Efficacy and QoL Study of Human recAP in the Treatment of Patients With SA-AKI (STOP-AKI)

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ClinicalTrials.gov Identifier: NCT02182440
Recruitment Status : Completed
First Posted : July 8, 2014
Last Update Posted : December 6, 2017
Sponsor:
Collaborator:
PPD
Information provided by (Responsible Party):
AM-Pharma

Brief Summary:
The purpose of this study is to determine whether recombinant Alkaline Phosphatase (recAP) is effective and save, and to determine the most effective dose, in the treatment of patients with acute kidney injury caused by sepsis.

Condition or disease Intervention/treatment Phase
Acute Kidney Injury Biological: recAP Other: Placebo Phase 2

Detailed Description:

Design:

Adaptive trial with two stages and interim analysis

  • Stage 1: four arms; three dose groups and placebo. n=30/arm. (n=120)
  • Interim analysis based on 120 subjects, with continued recruitment, adding 11 subjects to Stage 1 safety population (n=131): to evaluate safety and select dose for stage 2
  • Stage 2: one dose group and placebo. N=85/arm. (n=170) Total n in the study: 301.

Primary objectives

  • To investigate the effect of recAP on renal function (measured creatinine clearance D1-D7 period, incidence and duration of renal replacement therapy (RRT) over 28 days, eGFR at D60 and D90) and related clinical parameters (ICU stay, Hospital stay, Mechanical ventilation over 28 days, SOFA and SAPS2 scores 28 days) in patients with SA-AKI.
  • To determine effective therapeutic dose(s) of recAP.

Secondary objectives

  • To investigate the safety and tolerability of recAP in patients with SA AKI. (assessed by independent Data Monitoring Board, adverse events over 90 days study period, laboratory values, ECG, physical examniations, vital signs, Anti Drug Antibodies)
  • To investigate the pharmacokinetic profile (PK) of recAP in a subset of patients (part 1, n=120) with SA AKI. (Population PK; AUC D1-7, Cmax, Cmin, Tmax, terminal T1/2)
  • To investigate the immunogenic potential of recAP in patients with SA AKI. (anti-drug antibodies at D14, D28, D60 and D90)
  • To investigate the effect on quality of life (using the EuroQol, EQ-5D) following study inclusion, at ICU discharge, and Day 90.

Other objectives

• To evaluate whether specific patient groups can be identified that benefit most from recAP treatment or patient groups that are non-responders


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 301 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A DB Four-Arm, Parallel Group, Proof of Concept, Dose-Finding Adaptive Phase 2a/2b RCT to Investigate the Safety, Tolerability and Efficacy and Effect on QoL of Human Recombinant Alkaline Phosphatase in Patients With Sepsis-Associated AKI
Actual Study Start Date : December 18, 2014
Actual Primary Completion Date : May 25, 2017
Actual Study Completion Date : September 27, 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Sepsis

Arm Intervention/treatment
Placebo Comparator: Placebo
1 hour IV infusion once daily for 3 days
Other: Placebo
1 hour IV infusion once daily for 3 days

Experimental: 0.4 mg/kg (250 U/kg) recAP
1 hour IV infusion once daily for 3 days
Biological: recAP
One hour infusions once daily for three days
Other Name: Recombinant Alkaline Phosphatase

Experimental: 0.8 mg/kg (500 U/kg) recAP
1 hour IV infusion once daily for 3 days
Biological: recAP
One hour infusions once daily for three days
Other Name: Recombinant Alkaline Phosphatase

Experimental: 1.6 mg/kg (1000 U/kg) recAP
1 hour IV infusion once daily for 3 days
Biological: recAP
One hour infusions once daily for three days
Other Name: Recombinant Alkaline Phosphatase




Primary Outcome Measures :
  1. Measured creatinine clearance (based on urine volume and creatinine concentrations) [ Time Frame: 7 days ]
    Urine collected daily for 4-8 hour periods. Creatinine clearance (ml/min) is calculated from urine volume, plasma and urinary creatinine concentrations.


Secondary Outcome Measures :
  1. Incidence of renal replacement therapy (RRT) [ Time Frame: 28 days ]
    Start and stop of RRT is per criteria as defined in the protocol


Other Outcome Measures:
  1. To investigate the immunogenic potential of recAP [ Time Frame: D14, D28, D60, D90 ]
    Central laboratory anti-drug antibodies at visits on Days 14, 28, 60, and 90. Samples taken on Days 60 and 90 will only be analyzed in case of a positive result on Day 14

  2. Quality of Life [ Time Frame: pre study, ICU discharge, D90 ]
    EQ-5D



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Signed Informed Consent Form (patient, legal representative or independent investigator)
  2. Age 18 to 85 years, inclusive
  3. Is admitted to the ICU or Intermediate Care Unit
  4. Has diagnosis of sepsis (< 96 hrs prior to first study drug), according to criteria defined by the American College of Chest Physicians/Society of Critical Care Medicine:

    1. Has a proven or strongly suspected bacterial infection.
    2. Has at least 2 of 4 SIRS criteria 72 hrs < screening and 96 hrs < first study drug
  5. First diagnosis of AKI: AKI Stage 1 or greater, according to the AKIN criteria (time-window adjusted):

    1. Increase in serum creatinine > 26.2 µmol/L (0.30 mg/dL) in 48 hrs prior to screening, or
    2. Increase in serum creatinine to > 150% (> 1.5-fold) from reference creatinine value in 48 hrs prior to screening
    3. Urinary output < 0.5 mL/kg/h for > 6 hours following adequate fluid resuscitation
  6. Continuing AKI needs to be confirmed by a confirmative fluid corrected serum creatinine measure, or
  7. When the AKI diagnosis was made according to the AKIN urine output criteria (urinary output < 0.5 mL/kg/h for > 6 hours), the oliguria or anuria should still meet the AKIN urine output criteria prior to randomization.

Exclusion Criteria:

  1. Woman of childbearing potential with a positive pregnancy test, pregnant, or breastfeeding.
  2. Weighs more than 115 kg (253 lb).
  3. Has life support limitations.
  4. Is known to be human immunodeficiency virus positive.
  5. Has urosepsis.
  6. Is already on dialysis (RRT) or anticipated to receive RRT within 24 hours after study drug dosing due to the underlying disease.
  7. Is receiving immunosuppressant treatment or is on chronic high doses of steroids equivalent to prednisone/prednisolone 0.5 mg/kg/day, including solid organ transplant patients. Patients with septic shock treated with hydrocortisone (e.g., 3 × 100 mg) can be included.
  8. Is expected to have rapidly fatal outcome (within 24 hours).
  9. Has known, confirmed fungal sepsis.
  10. Has advanced chronic liver disease, confirmed by a Child-Pugh score of 10 to 15.
  11. Has acute pancreatitis with no established source of infection.
  12. Has participated in another investigational study within 30 days prior to enrollment.
  13. Is not expected to survive for 28 days due to medical conditions other than SA AKI, including cancer, end-stage cardiac disease, cardiac arrest requiring cardiopulmonary resuscitation or with pulseless electrical activity or asystole within the past 30 days, end stage lung disease, and end stage liver disease.
  14. Has known prior history of Chronic Kidney Disease with a documented estimated Glomerular Filtration Rate (eGFR) < 60 mL/min by Modification of Diet in Renal Disease MDRD or CKD-EPI formula, known GFR < 60 mL/min, or a known history of persistent creatinine level > 150 µmol/L (1.70 mg/dL) for reasons other than the current sepsis condition.
  15. Has diagnosis of malaria or other parasite infections.
  16. Has burns on > 20% of body surface.
  17. Has had AKI diagnosis according to inclusion criteria > 24 hours prior to study drug administration.
  18. Is anticipated to be treated with non-continuous RRT from Day 1 to Day 7.
  19. During Day 1 to Day 7 continuous RRT is anticipated to be started or stopped not according to per protocol criteria.
  20. The AKI is most likely attributable to other causes than sepsis, such as nephrotoxic drugs and renal perfusion-related.
  21. Improvement in serum creatinine of at least 0.30 mg/dL or (26.2 µmol/L) prior to administration of the study drug.
  22. Patients who use nephrotoxic medication and who fulfill the SA-AKI inclusion criteria at screening are not eligible if the use of this nephrotoxic medication is to continue when alternative, medically appropriate, non-nephrotoxic medication is available.
  23. Has a history of known IV drug abuse.
  24. Is an employee or family member of the investigator or study site personnel.
  25. Has active hematological malignancy.

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): NCT02182440


  Show 48 Study Locations
Sponsors and Collaborators
AM-Pharma
PPD
Investigators
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Study Director: Jacques Arend, MD DiMD AM Pharma BV
Study Chair: Peter Pickkers, Prof MD. PhD Department Intensive Care, Radboud University Medical Center

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: AM-Pharma
ClinicalTrials.gov Identifier: NCT02182440     History of Changes
Other Study ID Numbers: AP-recAP-AKI-02-01
2014-000761-40 ( EudraCT Number )
First Posted: July 8, 2014    Key Record Dates
Last Update Posted: December 6, 2017
Last Verified: December 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Keywords provided by AM-Pharma:
SA-AKI
Sepsis
AKI
Recombinant Alkaline Phosphatase
recAP

Additional relevant MeSH terms:
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Acute Kidney Injury
Renal Insufficiency
Kidney Diseases
Urologic Diseases