Study to Evaluate the Safety and Efficacy of Liquid Alpha1-Proteinase Inhibitor (Human) in Hospitalized Participants With Coronavirus Disease (COVID-19)

COVID-19 Clinical Trial

Official title:

A Multicenter, Randomized, Double-blind, Placebo-Controlled, Parallel Group Study to Evaluate the Safety and Efficacy of Liquid Alpha1-Proteinase Inhibitor (Human) Plus Standard Medical Treatment (SMT) Versus Placebo Plus SMT in Hospitalized Subjects With COVID-19

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04547140
• Other study ID #: GC2006
• Status: Terminated
• Phase: Phase 2
• Start date: January 29, 2021
• Est. completion date: January 28, 2022

Study information

• Verified date: March 2023
• Source: Grifols Therapeutics LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of the study is to determine if Liquid Alpha1-Proteinase Inhibitor (Human) (Liquid Alpha1-PI) plus SMT can reduce the proportion of participants dying or requiring intensive care unit (ICU) admission on or before Day 29 or who are dependent on high flow oxygen devices or invasive mechanical ventilation on Day 29 versus placebo plus SMT in hospitalized participants with COVID-19.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 57
• Est. completion date: January 28, 2022
• Est. primary completion date: December 13, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Hospitalized male or female participant = 18 years of age at time of screening who is being treated for COVID-19. Participants must be screened within 48 hours (= 48 hours) of hospital admission.

2. Has laboratory-confirmed novel coronavirus {SARS-CoV-2} infection as determined by qualitative polymerase chain reaction (PCR) (reverse transcriptase [RT]-PCR), or other commercial or public health assay approved by regulatory authorities as a diagnostic test for COVID-19 in any specimen during the current hospital admission OR 96 hours prior to the hospital admission date and prior to randomization (the SARS-CoV-2 test results must be performed by a hospital laboratory and the documentation available).

3. COVID-19 illness (symptoms) of any duration, including both of the following: a) Radiographic infiltrates by imaging (chest X-Ray, computed tomography (CT) scan, etc.) and/or clinical assessment (evidence of rales/crackles on exam) with peripheral oxygen saturation by pulse oximetry (SpO2) <94% on room air; b) Any one of the following related to COVID-19: i. Ferritin > 400 nanogram per milliliter (ng/mL), ii. lactate dehydrogenase (LDH) > 300 units per liter (U/L), iii. D-Dimers > reference range, or iv. C-reactive protein (CRP) > 40 milligram per liter (mg/L).

4. Participant provides informed consent prior to initiation of any study procedures.

5. Female participants of childbearing potential (and males with female partners of childbearing potential) must agree to use of acceptable contraception methods during study (example, oral, injectable, or implanted hormonal methods of contraception, placement of an intrauterine device or intrauterine system, condom or occlusive cap with spermicidal foam/gel/film/cream/suppository, male sterilization, or true abstinence) throughout the study.

Exclusion Criteria:

1. Participants requiring invasive mechanical ventilation or ICU admission or with partial pressure of arterial oxygen/ fraction of inspired oxygen (PaO2/FIO2) = 150 mmHg (i.e., arterial oxygen in millimeter of mercury (mmHg) divided by fraction inspired oxygen concentration [example, 0.21 for room air]).

2. Clinical evidence of any significant acute or chronic disease that, in the opinion of the investigator, may place the participant at undue medical risk.

3. The participant has had a known serious anaphylactic reaction to blood, any blood-derived or plasma product, or known selective immunoglobulin A (IgA) deficiency with anti-IgA antibodies.

4. A medical condition in which the infusion of additional fluid is contraindicated (example, decompensated congestive heart failure or renal failure with fluid overload). This includes currently uncontrolled congestive heart failure New York Heart Association Class III or IV stage heart failure.

5. Shock that is unresponsive to fluid challenge and/or multiple vasopressors and accompanied by multiorgan failure considered not able to be reversed by the Principal Investigator.

6. Known alpha-1 antitrypsin deficiency for which the participant is already receiving alpha1-proteinase inhibitor augmentation therapy.

7. Women who are pregnant or breastfeeding. Female participants of child-bearing potential must have a negative test for pregnancy blood or urine human chorionic gonadotropin (HCG)-based assay at screening/baseline visit.

8. Participants for whom there is limitation of therapeutic effort such as "Do not resuscitate" status.

9. Currently participating in another interventional clinical trial with investigational medical product or device.

10. Participants previously requiring long-term oxygen therapy (home oxygen therapy).

11. History (within the last 2 years) of myocardial infarction, unstable angina, stroke or transient ischemic attacks, pulmonary embolism or deep venous thrombosis.

12. Participant has medical condition (other than COVID-19) that is projected to limit lifespan to = 1 year.

13. Systolic blood pressure < 100 mm Hg or > 160 mm Hg (uncontrolled hypertension) at the time of Screening.

14. Alanine aminotransferase (ALT) = 2 times the upper limit of normal (ULN).

15. Any elevation of total bilirubin at the time of Screening.

16. Estimated glomerular filtration rate (eGFR) < 45 mL/min (or participant is dependent on dialysis/renal replacement therapy) at the time of Screening. eGFR is calculated by the Cockcroft-Gault equation.

17. Hemoglobin < 10 g/dL at the time of Screening.

18. Absolute neutrophil count < 1000/mm^3 at the time of Screening.

19. Platelet count < 75,000/mm^3 at the time of Screening.

20. Participant has history of drug or alcohol abuse within the past 24 months.

21. Participant is unwilling to commit to follow-up visits.

22. Known history of prothrombin gene mutation 20210, homozygous Factor V Leiden mutations, antithrombin III deficiency, protein C deficiency, protein S deficiency or antiphospholipid syndrome.

Related Conditions & MeSH terms

• Alpha 1-Antitrypsin Deficiency
• COVID-19

Intervention

Biological:
• Liquid Alpha1-Proteinase Inhibitor (Human)
Intravenous infusion 120 mg/kg

Drug:
• Placebo
Intravenous infusion
• Standard Medical Treatment
SMT

Locations

Country	Name	City	State
Brazil	AngioCor Blumenau	Blumenau	Santa Catarina
Brazil	Hospital Dia do Pulmão	Blumenau
Brazil	Universidade Estadual São Paulo - Campus de Botucatu	Botucatu	São Paulo
Brazil	Sociedade Literaria e Caritativa Santo Agostinho	Criciúma	Santa Catarina
Brazil	Hospital Alemao Oswaldo Cruz	São Paulo
Brazil	Universidade Federal de Sao Paulo	São Paulo
Chile	Hospital Padre Hurtado	Santiago
Chile	Hospital Carlos Van Buren	Valparaíso
Colombia	Fundación Oftalmológica de Santander	Bucaramanga	Santander
Mexico	Unidad Medica para la Salud Integral	San Nicolás de los Garza
United States	Birmingham VA	Birmingham	Alabama
United States	Hannibal Clinic	Hannibal	Missouri
United States	Kansas City VA	Kansas City	Missouri
United States	Sparrow Hospital	Lansing	Michigan
United States	Memphis VA	Memphis	Tennessee
United States	University of Miami Hospital	Miami	Florida
United States	Columbia University Medical Center	New York	New York
United States	CHI Health Center	Omaha	Nebraska
United States	St. Joseph's Hospital	Phoenix	Arizona
United States	University of Utah	Salt Lake City	Utah

Sponsors (1)

Lead Sponsor	Collaborator
Grifols Therapeutics LLC

Countries where clinical trial is conducted

United States,  Brazil,  Chile,  Colombia,  Mexico, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants Dying or Requiring Intensive Care Unit (ICU) Admission		Up to Day 29
Primary	Percentage of Participants Who Are Dependent on High Flow Oxygen Devices or Invasive Mechanical Ventilation		Day 29
Secondary	Change From Baseline in National Early Warning Score (NEWS)	NEWS is clinical scoring developed to improve detection of deterioration in ill participant. It is based on 7 clinical parameters: Respiration rate, oxygen saturation, supplemental oxygen, systolic blood pressure (BP), pulse rate, level of consciousness, and temperature. A score of 0 and 2 was allocated to supplemental oxygen, 0 and 3 for level of consciousness and score of 0, 1, 2 and 3 for remaining parameters (i.e. respiration rate, oxygen saturation, systolic BP, pulse rate and temperature) where 0 = normal health condition to 3 = worst health condition; Higher scores indicated more severity. All scores were summed to get an aggregate score. Aggregate NEWS score ranged from 0 to 20, with higher scores indicating more severity/higher risk.	Baseline, Days 15 and 29
Secondary	Time to Clinical Response as Assessed by NEWS Score = 2 Maintained for 24 Hours	Time to clinical response was reported at 50th percentile in days.	Up to Day 29
Secondary	Time to Hospital Discharge	Time to hospital discharge is defined as duration of hospitalization from Day 1 through Day 29.	Up to Day 29
Secondary	Duration of ICU Stay	Duration of ICU stay in days is analyzed for participants admitted to ICU post randomization.	Up to Day 29
Secondary	Duration of Any Oxygen Use		Up to Day 30
Secondary	Duration of Mechanical Ventilation	Duration of Mechanical Ventilation is analyzed for participants requiring mechanical ventilation post randomization.	Up to Day 29
Secondary	Mean Change From Baseline in Ordinal Scale	The ordinal scale is a 7-point scale ranging from 1 to 7 used to measure clinical status based on the following points: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen; 6) Not hospitalized, limitation on activities; 7) Not hospitalized, no limitations on activities. Higher score indicated no severe illness. Mean change in Ordinal scale was evaluated by fitting a linear mixed-effects model for repeated measures (MMRM).	Baseline, Days 15 and 29
Secondary	Absolute Change From Baseline in Ordinal Scale	The ordinal scale is a 7-point scale ranging from 1 to 7 used to measure clinical status based on the following points: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or ECMO; 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen; 6) Not hospitalized, limitation on activities; 7) Not hospitalized, no limitations on activities. Higher score indicated no severe illness.	Baseline, Days 15 and 29
Secondary	Percentage of Participants in Each Severity Category of the 7-point Ordinal Scale	The ordinal scale is a 7-point scale ranging from 1 to 7 used to measure clinical status based on the following points: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or ECMO 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen; 6) Not hospitalized, limitation on activities; 7) Not hospitalized, no limitations on activities. The percentages are rounded off to the single decimal point.	Day 15 and Day 29
Secondary	Time to Sustained Normalization of Temperature	Time to sustained normalization of temperature was reported at 50th percentile in days.	Up to Day 29
Secondary	Percentage of Participants Who Experienced Sustained Normalization of Fever	Normalization of fever is defined as temperature < 36.6 °C armpit, < 37.2 °C oral, or < 37.8 °C rectal sustained for at least 24 hours.	Up to Day 29
Secondary	Number of Participants Who Develop Acute Respiratory Distress Syndrome (ARDS)	ARDS was defined based on Berlin criteria (chest imaging, origin of edema, oxygenation).	Up to Day 29
Secondary	Time to Clinical Progression	Time to clinical progression is defined as the time to death, mechanical ventilation, or ICU admission. Time to clinical progression was reported at 50th percentile in days.	Up to Day 29