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 |
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Recruitment Status :
Completed
First Posted : July 8, 2014
Results First Posted : March 23, 2020
Last Update Posted : March 23, 2020
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Sponsor:
AM-Pharma
Collaborator:
PPD
Information provided by (Responsible Party):
AM-Pharma
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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 |
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 : | 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
| Arm | Intervention/treatment |
|---|---|
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Placebo Comparator: Placebo
1 hour IV infusion once daily for 3 days
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Other: Placebo
1 hour IV infusion once daily for 3 days |
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Experimental: 0.4 mg/kg (250 U/kg) recAP
1 hour IV infusion once daily for 3 days
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Biological: recAP
One hour infusions once daily for three days
Other Name: Recombinant Alkaline Phosphatase |
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Experimental: 0.8 mg/kg (500 U/kg) recAP
1 hour IV infusion once daily for 3 days
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Biological: recAP
One hour infusions once daily for three days
Other Name: Recombinant Alkaline Phosphatase |
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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 :
- 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.
Secondary Outcome Measures :
- 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.
Other Outcome Measures:
- 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:
- had eGFR < 60 mL/min (calculated by using the CKD-EPI formula) or
- became dialysis dependent up to Day 60 or
- 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:
- had eGFR <60 ml/min at Day 90, estimated by the CKD-EPI formula based on a serum creatinine or
- was dialysis dependent up to Day 90 or
- was hospitalized for a new episode of acute kidney injury prior to Day 90 or
- 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.
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:
- Signed Informed Consent Form (patient, legal representative or independent investigator)
- Age 18 to 85 years, inclusive
- Is admitted to the ICU or Intermediate Care Unit
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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:
- Has a proven or strongly suspected bacterial infection.
- Has at least 2 of 4 SIRS criteria 72 hrs < screening and 96 hrs < first study drug
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First diagnosis of AKI: AKI Stage 1 or greater, according to the AKIN criteria (time-window adjusted):
- Increase in serum creatinine > 26.2 µmol/L (0.30 mg/dL) in 48 hrs prior to screening, or
- Increase in serum creatinine to > 150% (> 1.5-fold) from reference creatinine value in 48 hrs prior to screening
- Urinary output < 0.5 mL/kg/h for > 6 hours following adequate fluid resuscitation
- Continuing AKI needs to be confirmed by a confirmative fluid corrected serum creatinine measure, or
- 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:
- Woman of childbearing potential with a positive pregnancy test, pregnant, or breastfeeding.
- Weighs more than 115 kg (253 lb).
- Has life support limitations.
- Is known to be human immunodeficiency virus positive.
- Has urosepsis.
- Is already on dialysis (RRT) or anticipated to receive RRT within 24 hours after study drug dosing due to the underlying disease.
- 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.
- Is expected to have rapidly fatal outcome (within 24 hours).
- Has known, confirmed fungal sepsis.
- Has advanced chronic liver disease, confirmed by a Child-Pugh score of 10 to 15.
- Has acute pancreatitis with no established source of infection.
- Has participated in another investigational study within 30 days prior to enrollment.
- 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.
- 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.
- Has diagnosis of malaria or other parasite infections.
- Has burns on > 20% of body surface.
- Has had AKI diagnosis according to inclusion criteria > 24 hours prior to study drug administration.
- Is anticipated to be treated with non-continuous RRT from Day 1 to Day 7.
- During Day 1 to Day 7 continuous RRT is anticipated to be started or stopped not according to per protocol criteria.
- The AKI is most likely attributable to other causes than sepsis, such as nephrotoxic drugs and renal perfusion-related.
- Improvement in serum creatinine of at least 0.30 mg/dL or (26.2 µmol/L) prior to administration of the study drug.
- 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.
- Has a history of known IV drug abuse.
- Is an employee or family member of the investigator or study site personnel.
- 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
Locations
Show 58 study locations
Sponsors and Collaborators
AM-Pharma
PPD
Investigators
| Study Director: | Jacques Arend, MD DiMD | AM Pharma BV | |
| Study Chair: | Peter Pickkers, Prof MD. PhD | Department Intensive Care, Radboud University Medical Center |
Study Documents (Full-Text)
Documents provided by AM-Pharma:
Documents provided by AM-Pharma:
Study Protocol [PDF] February 3, 2016
Statistical Analysis Plan [PDF] September 27, 2017
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | AM-Pharma |
| ClinicalTrials.gov Identifier: | NCT02182440 |
| Other Study ID Numbers: |
AP-recAP-AKI-02-01 2014-000761-40 ( EudraCT Number ) |
| First Posted: | July 8, 2014 Key Record Dates |
| Results First Posted: | March 23, 2020 |
| Last Update Posted: | March 23, 2020 |
| Last Verified: | March 2020 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Undecided |
Keywords provided by AM-Pharma:
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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 |