Plasma for Early Treatment in Non-hospitalised Mild or Moderate COVID-19 Patients

Phase 2

Completed

• Conditions: SARS-CoV-2 Infection; Safety and Efficacy
• Interventions: Biological: Convalescent anti-SARS-CoV-2 MBT plasma; Other: Control Group

• Registration Number: NCT04621123
• Lead Sponsor: Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia

Brief Summary

This is a prospective, randomized (1:1), double blind study of Convalescent anti-SARS-CoV-2 MBT Plasma (also known as convalescent plasma) plus standard medical treatment (SMT) versus placebo plus SMT in mild or moderate COVID-19 patients who are non-hospitalised. Subjects with confirmed infection by SARS-CoV-2 will receive SMT plus a total of 200-300 mL of convalescent plasma that has been pathogen-inactivated using MBT or placebo.

Approximately 474 individuals will be randomized (1:1) with an interim analysis after the first 60 subjects (30 in each arm).

The sample size will be re-assessed upon interim analysis. Approximately 135 individuals from selected study sites will be included in the substudy to assess the immune response and the methods of sampling.

This is a prospective, randomized (1:1), double blind study of Convalescent anti-SARS-CoV-2 MBT Plasma (also known as convalescent plasma) plus standard medical treatment (SMT) versus placebo plus SMT in mild or moderate COVID-19 patients who are non-hospitalised. Subjects with confirmed infection by SARS-CoV-2 will receive SMT plus a total of 200-300 mL of convalescent plasma that has been pathogen-inactivated using MBT or placebo.

Approximately 474 individuals will be randomized (1:1) with an interim analysis after the first 60 subjects (30 in each arm).

The sample size will be re-assessed upon interim analysis. Approximately 135 individuals from selected study sites will be included in the substudy to assess the immune response and the methods of sampling.

The investigational product will be administered by IV infusion at baseline. Participants will continue their standard medical treatment (SMT) for SARS-CoV-2 infection as prescribed by their regular physician. If applicable, SMT may be modified during the study, depending on personal requirements, the severity and progression of the disease, and need for hospitalization.

Subjects' participation (from inclusion/baseline visit to the end-of-study visit) will be up to 60 days.

Detailed Description

This is a prospective, randomized (1:1), double blind study of Convalescent anti-SARS-CoV-2 MBT Plasma (also known as convalescent plasma) plus standard medical treatment (SMT) versus placebo plus SMT in mild or moderate COVID-19 patients who are non-hospitalised. Subjects with confirmed infection by SARS-CoV-2 will receive SMT plus a total of 200-300 mL of convalescent plasma that has been pathogen-inactivated using MBT or placebo.

Study candidates will voluntarily express their interest in participating in the study through the study website or will be offered to participate at the emergency (ER) and out-patient departments (OPD) of the participating hospitals. Candidates registered on the website will be contacted by study physicians by phone to inform them about the study and check their suitability for the study. Suitable candidates will be scheduled an inclusion/baseline visit in which informed consent will be obtained (i.e., the paper informed consent will be signed), and their eligibility will be confirmed. Candidates identified through ER and OPD departments will undergo an inclusion/baseline visit, where the informed consent will be obtained and eligibility will be checked. A subgroup of eligible candidates from selected study sites will be offered participation in the substudy to assess the immune response and the methods of sampling.

Blood and nasopharyngeal samples will be obtained from all eligible candidates. Eligible candidates will be randomized and administered an intravenous (IV) infusion at baseline (convalescent plasma or placebo). Both the investigator and the participant will be blinded to the study treatment.

Specifically, subjects randomized to combination convalescent anti-SARS-CoV-2 MBT plasma plus SMT will undergo an ABO compatibility test and will receive a single infusion of 200 to 300 ml of ABO-compatible convalescent plasma. Subjects randomized to placebo plus SMT will receive a single infusion of 200 to 300 ml of sterile saline solution 0.9%. Infusion will be administered at baseline, using standard procedures for administration of fresh frozen plasma. Small adults weighing less than 45 kg will receive one infusion of 5 ml of convalescent plasma or placebo per kilogram of body weight.

Participants will be trained on the completion of symptoms diary card and safety diary card.

The participants of the substudy will be drawn an extra tube of blood sample and will be trained on self-collection of middle turbinate (MT) swabs and saliva, and self-collected samples will be obtained.

The symptoms and safety diary card will be filled by the participants daily from baseline to day 14. On follow-up visits on days 3, 7, 14, and 28, all participants will be assessed for clinical and safety outcomes. These visits will be all by telephone except for the day 7 and day 28 visits that will be at home and at hospital, respectively, where additionally blood samples (only on day 7) and nasopharyngeal swabs will be collected.

At day 60 visit, all participants will be assessed by telephone for health-status outcome.

For the participants of the substudy, on day 7, an extra tube of blood sample will be obtained and they will be asked to self-collect MT swabs and saliva. And on day 60, an extra tube of blood sample will be obtained during an additional home or hospital visit.

Approximately 474 individuals will be randomized (1:1) with an interim analysis after the first 60 subjects (30 in each arm).

The sample size will be re-assessed upon interim analysis. Approximately 135 individuals from selected study sites will be included in the substudy to assess the immune response and the methods of sampling.

The investigational product will be administered by IV infusion at baseline. Participants will continue their standard medical treatment (SMT) for SARS-CoV-2 infection as prescribed by their regular physician. If applicable, SMT may be modified during the study, depending on personal requirements, the severity and progression of the disease, and need for hospitalization.

Subjects' participation (from inclusion/baseline visit to the end-of-study visit) will be up to 60 days.

Study Timeline

• Study First Submitted: 2020-11-04
• Study First Submitted QC: 2020-11-06
• Study First Posted: 2020-11-09
• Study Start: 2020-11-10
• Primary Completion: 2021-05-31
• Study Completion: 2021-07-28
• Status Verified: 2021-09
• Last Update Submitted: 2021-09-04
• Last Update Posted: 2021-09-08

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 384

Inclusion Criteria

1. 1. Adult male or female individuals of ≥50 years old.
2. 2. In women of childbearing potential1, negative pregnancy test at inclusion/baseline.
3. 3. Has confirmed SARS-CoV-2 infection as determined by PCR or validated antigen rapid diagnostic test2 from nasopharyngeal swabs ≤5 days prior to inclusion/baseline visit.

4. 4. Symptomatic with mild or moderate COVID-19 with symptoms onset date ≤ 7 days prior to inclusion/baseline visit.

   5. a. Mild COVID-19: Individuals who have any of the common signs and/or symptoms of COVID-19 (i.e., fever, cough, sore throat, malaise, headache, muscle pain) without shortness of breath, dyspnoea, or abnormal chest imaging.

   6. Moderate COVID-19: Individuals who have evidence of lower respiratory disease by clinical assessment or imaging and a saturation of oxygen (SpO2) ≥94% on room air at sea level.

5. 5. Willing to comply with the requirements of the protocol and available for follow-up for the planned duration of the study.
6. 6. Has understood the information provided and capable of giving informed consent.

1 A woman will be considered of childbearing potential if not permanently sterilized nor postmenopausal. Permanent sterilization methods include tubal ligation, hysterectomy and bilateral oophorectomy. Postmenopausal is defined as 12 months with no menses without an alternative medical cause.

2 PanbioTM COVID-19 Ag Rapid Test (Abbott), STANDARDTM Q COVID-19 Ag Test (Roche) or any other CE marketed test for SARS-CoV-2 Ag detection.

Exclusion Criteria

1. If female, pregnant, breastfeeding, or planning a pregnancy during the study.

2. Severe or critical COVID-19:

   1. Severe COVID-19: respiratory frequency >30 breaths per minute, SpO2 <94% on room air at sea level, ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) <300 mmHg, or lung infiltrates >50%.
   2. Critical COVID-19: respiratory failure, septic shock, and/or multiple organ dysfunction.

3. Current hospital admission for any cause.

4. History of previous confirmed SARS-CoV-2 infection.

5. History of significantly abnormal liver function (Child Pugh C).

6. History of chronic kidney disease (CKD) ≥ stage 4, or need of dialysis treatment.

7. Any pre-existing condition that increases risk of thrombosis.

8. History of allergic reactions to blood or plasma products or methylene blue.

9. Known IgA deficiency with anti-IgA antibodies.

10. Medical conditions for which 300ml of intravenous fluid is considered dangerous (i.e., decompensated heart failure or renal failure with fluid overload).

11. Inability to consent and/or comply with study requirements, in the opinion of the investigator.

12. Currently participating or planning to participate in any interventional study for the treatment of COVID-19 or SARS-CoV-2 infection until day 60.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Experimental group	Convalescent anti-SARS-CoV-2 MBT plasma	Subjects randomized to convalescent anti-SARS-CoV-2 MBT plasma plus SMT will receive one infusion of 200 to 300 ml of ABO-compatible convalescent plasma obtained from a convalescent donor.
Control Group	Control Group	Subjects randomized to placebo plus SMT will receive one infusion of 200 to 300 ml of sterile saline solution 0.9%.

Primary Outcome Measures

Name	Time	Method
SARS-CoV-2 viral load (safety and efficacy)	Day 7	Assess the therapeutic potential of early administration of convalescent MBT plasma in reducing SARS-CoV-2 viral load at day 7, measured by quantitative RT-PCR (RT-qPCR) in non-hospitalised mild or moderate COVID-19 patients.
Hospitalization rate (safety and efficacy)	Day 28	Assess the therapeutic potential of early administration of convalescent MBT plasma in reducing the rate of hospitalization in non-hospitalised mild or moderate COVID-19 patients.

Secondary Outcome Measures

Name	Time	Method
COVID-19 symptoms severity score (safety and efficacy)	Day 14	Change in COVID-19 symptoms severity score, assessed with the COVID-19 daily self-score tool (FLU- patient-reported outcome measure (FLU-PRO©) PLUS instrument), certified-Spanish translation. COVID-19 daily self-score tool to assess symptom severity across six body systems: nose, throat, eyes, chest/respiratory, gastrointestinal, and body/systemic. Data on the presence/absence of symptoms, symptom profiles, and change over time.; Items 1-27 are Likert scale questions to score symptom severity (rated 0-4): 0=not at all;4=very much. Items 28-32 are also Likert scale questions (rated 0-4) measuring frequency of specific daily symptoms: 0=never or 0 times;4=always or 4 times. Items 33 and 34 measure the presence/absence of COVID-19 specific symptoms: 0=no;1=yes. Total maximum score of FLU-PRO© PLUS 134
Resolution of symptoms (safety and efficacy)	Day 28	Time to complete resolution of symptoms
Absolute neutralization titers against SARS-CoV-2 in plasma (safety and efficacy)	Baseline and Day 7	Intergroup comparison of absolute neutralization titers against SARS-CoV-2 in plasma in a subgroup of 135 participants
Titers of neutralizing antibodies against SARS-CoV-2 in plasma (safety and efficacy)	Baseline and Day 60	Change in titers of neutralizing antibodies against SARS-CoV-2 in plasma in a subgroup of 135 participants
Adverse events (AE) (safety and efficacy) Adverse events (AE) Adverse events (AE)	Day 28	Proportion of patients with adverse events (AE) and proportion of grade ≥4 AE, based on the FDA Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers scale
Prealbumin (safety and efficacy)	Baseline and Day 7	Change in inflammatory prognostic markers (prealbumin)
D-dimer (safety and efficacy)	Baseline and Day 7	Change in inflammatory prognostic markers (D-dimer)
COVID-19 WHO Clinical progression scale score (safety and efficacy)	Day 60	Change in COVID-19 World Health Organization WHO Clinical progression scale score to assess hospitalization rate (i.e. who reach a score ≥4).; * Minimum to maximum scores below: * Score 0 (uninfected) - Uninfected; no viral RNA detected; * Score 1 (ambulatory mild disease) - Asymptomatic; viral RNA detected; * Score 2 (ambulatory mild disease) - Symptomatic; independent; * Score 3 (ambulatory mild disease) - Symptomatic; assistance needed; * Score 4 (hospitalised: moderate disease) - Hospitalised; no oxygen therapy; * Score 5 (hospitalised: moderate disease) - Hospitalised; oxygen by mask or nasal prongs; * Score 6 (hospitalised: severe diseases) - Hospitalised; oxygen by NIV or high flow; * Score 7 (hospitalised: severe diseases) - Intubation Score 8 (hospitalised: severe diseases) - Mechanical ventilation pO2/FiO2 \<150 (SpO2/FiO2 \<200) or vasopressors; * and mechanical ventilation, pO2/FiO2 ≥150 or SpO2/FiO2 ≥200
Ferritin (safety and efficacy)	Baseline and Day 7	Change in inflammatory prognostic markers (ferritin)
Leukocyte count (safety and efficacy)	Baseline and Day 7	Change in inflammatory prognostic markers (Leukocyte count)
Death rate (safety and efficacy)	Day 60	Death rate
Interleukin 6 (IL-6) (safety and efficacy)	Baseline and Day 7	Change in inflammatory prognostic markers (Interleukin 6 (IL-6))
C reactive protein (CRP) (safety and efficacy)	Baseline and Day 7	Change in inflammatory prognostic markers (C reactive protein (CRP))
Reduction of SARS-CoV-2 viral load (safety and efficacy)	Baseline and Day 28	Reduction of SARS-CoV-2 viral load in nasopharyngeal swabs at day 28 after start of treatment, as determined by RT-qPCR
Lymphocyte count (safety and efficacy)	Baseline and Day 7	Change in inflammatory prognostic markers (Lymphocyte count)
SARS-CoV-2 viral load of self-collected middle turbinate (MT) swab and saliva samples compared to nasopharyngeal swabs collected by a healthcare worker (safety and efficacy)	Baseline and Day 7	Agreement and SARS-CoV-2 viral load of self-collected middle turbinate (MT) swab and saliva samples compared to nasopharyngeal swabs collected by a healthcare worker in a subgroup of 135 participants; Outcome 18: Secondary Outcome Measure:

Trial Locations

Locations (4)

Germans Trias i Pujol Hospital; 🇪🇸 Badalona, Barcelona, Spain

CUAP Manresa (Planta 0 del CAP Bages); 🇪🇸 Manresa, Barcelona, Spain

Hospital Sant Bernabé (Hospital de Berga); 🇪🇸 Berga, Barcelona, Spain

Hospital Universitari de Bellvitge; 🇪🇸 Barcelona, Spain