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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02182440
Recruitment Status : Completed
First Posted : July 8, 2014
Results First Posted : March 23, 2020
Last Update Posted : March 23, 2020
Sponsor:
Collaborator:
PPD
Information provided by (Responsible Party):
AM-Pharma

Tracking Information
First Submitted Date  ICMJE June 27, 2014
First Posted Date  ICMJE July 8, 2014
Results First Submitted Date  ICMJE November 5, 2018
Results First Posted Date  ICMJE March 23, 2020
Last Update Posted Date March 23, 2020
Actual Study Start Date  ICMJE December 18, 2014
Actual Primary Completion Date May 25, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 4, 2020)
Area Under the Time Corrected Endogenous Creatinine Clearance From Day 1 to Day 7 (AUC1-7) [ Time Frame: 7 days ]
Primary endpoint is calculated as the average of the standardized endogenous creatinine clearance values over the first seven days between the placebo and 1.6 mg/kg recAP arm. Standardized endogenous creatinine clearance is assessed on each days from D1 to Day 7 during a 6 +/- 1 hour period and calculated in mL/min as the mean creatinine clearance over the period. The study started with 4 treatment arms of which 0.4 mg/kg recAP and the 0.8 mg/kg recAP were dropped after the interim analysis. The number of the patients in the dropped arm are respectively 30 and 32. Therefore the statistical analysis has been performed only on the placebo and 1.6 mg/kg group.
Original Primary Outcome Measures  ICMJE
 (submitted: July 3, 2014)
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.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 4, 2020)
Number of Participants Who Had Renal Replacement Therapy (RRT) During the Period Day 1 to Day 28, Inclusive [ Time Frame: 28 days ]
During the study the days on Renal Replacement Therapy (RRT) was recorded for each patients. During the first 7 days of the study (D1 to D7 included), patients were only allowed to receive continuous RRT, thereafter patients were also allowed to receive intermittent RRT. Standardization of RRT was attempted by providing guidelines to start and stop RRT (see protocol). Statistical analysis was only performed on the placebo and 1.6 mg/kg recAP arm due to the small number of patients treated with the doses of 0.4 mg/kg and 0.8 mg/kg recAP. Those two doses were dropped in part 2 of the study.
Original Secondary Outcome Measures  ICMJE
 (submitted: July 3, 2014)
Incidence of renal replacement therapy (RRT) [ Time Frame: 28 days ]
Start and stop of RRT is per criteria as defined in the protocol
Current Other Pre-specified Outcome Measures
 (submitted: March 4, 2020)
  • All-cause Mortality at Day 28 [ Time Frame: Day 28 ]
    Number of patients in the ITT set, who died in the period between day 1 to day 28. Statistical analysis was only performed on the placebo and 1.6 mg/kg recAP arm due to the small number of patients treated with the doses of 0.4 mg/kg and 0.8 mg/kg recAP. Those two doses were dropped in part 2 of the study.
  • All-cause Mortality at Day 90 [ Time Frame: Day 90 ]
    Number of patients in the ITT set, who died in the period between Day 1 and Day 90 Statistical analysis was only performed on the placebo and 1.6 mg/kg recAP arm due to the small number of patients treated with the doses of 0.4 mg/kg and 0.8 mg/kg recAP. Those two doses were dropped in part 2 of the study.
  • Number of Participants Meeting at Least One MAKE 60 Criteria [ Time Frame: Day 60 ]
    Make 60 is composed of patients that meet at least one of the following criteria at day 60:
    1. had eGFR < 60 mL/min (calculated by using the CKD-EPI formula) or
    2. became dialysis dependent up to Day 60 or
    3. died prior to Day 60 Statistical analysis was only performed on the placebo and 1.6 mg/kg recAP arm due to the small number of patients treated with the doses of 0.4 mg/kg and 0.8 mg/kg recAP. Those two doses were dropped in part 2 of the study.
  • Number of Patients Who Meet at Least One of the MAKE 90 Criteria [ Time Frame: Day 90 ]
    Make 90 includes patients who meet at least one of the following parameters at Day 90:
    1. had eGFR <60 ml/min at Day 90, estimated by the CKD-EPI formula based on a serum creatinine or
    2. was dialysis dependent up to Day 90 or
    3. was hospitalized for a new episode of acute kidney injury prior to Day 90 or
    4. died, prior to Day 90 Statistical analysis was only performed on the placebo and 1.6 mg/kg recAP arm due to the small number of patients treated with the doses of 0.4 mg/kg and 0.8 mg/kg recAP. Those two doses were dropped in part 2 of the study.
Original Other Pre-specified Outcome Measures
 (submitted: July 3, 2014)
  • 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
  • Quality of Life [ Time Frame: pre study, ICU discharge, D90 ]
    EQ-5D
 
Descriptive Information
Brief Title  ICMJE A Safety, Tolerability, Efficacy and QoL Study of Human recAP in the Treatment of Patients With SA-AKI
Official Title  ICMJE 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
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.
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

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Acute Kidney Injury
Intervention  ICMJE
  • Biological: recAP
    One hour infusions once daily for three days
    Other Name: Recombinant Alkaline Phosphatase
  • Other: Placebo
    1 hour IV infusion once daily for 3 days
Study Arms  ICMJE
  • Placebo Comparator: Placebo
    1 hour IV infusion once daily for 3 days
    Intervention: Other: Placebo
  • Experimental: 0.4 mg/kg (250 U/kg) recAP
    1 hour IV infusion once daily for 3 days
    Intervention: Biological: recAP
  • Experimental: 0.8 mg/kg (500 U/kg) recAP
    1 hour IV infusion once daily for 3 days
    Intervention: Biological: recAP
  • Experimental: 1.6 mg/kg (1000 U/kg) recAP
    1 hour IV infusion once daily for 3 days
    Intervention: Biological: recAP
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 4, 2016)
301
Original Estimated Enrollment  ICMJE
 (submitted: July 3, 2014)
290
Actual Study Completion Date  ICMJE September 27, 2017
Actual Primary Completion Date May 25, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 85 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Austria,   Belgium,   Czechia,   Finland,   France,   Germany,   Ireland,   Netherlands,   Spain,   United Kingdom,   United States
Removed Location Countries Czech Republic,   Italy
 
Administrative Information
NCT Number  ICMJE NCT02182440
Other Study ID Numbers  ICMJE AP-recAP-AKI-02-01
2014-000761-40 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party AM-Pharma
Study Sponsor  ICMJE AM-Pharma
Collaborators  ICMJE PPD
Investigators  ICMJE
Study Director: Jacques Arend, MD DiMD AM Pharma BV
Study Chair: Peter Pickkers, Prof MD. PhD Department Intensive Care, Radboud University Medical Center
PRS Account AM-Pharma
Verification Date March 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP