A Dose Finding, Efficacy and Safety Study of Ensovibep (MP0420) in Ambulatory Adult Patients With Symptomatic COVID-19

Phase 3TerminatedNCT04828161

Novartis Pharmaceuticals407 enrolled

Overview

The purpose of this study is to establish the antiviral efficacy of ensovibep against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in humans, identify the optimal dose, and demonstrate its clinical value for treating COVID-19 in adult ambulatory patients.

Primary objectives: Part A: The primary objective of this Part is to demonstrate superiority of ensovibep, compared to placebo, in reducing SARS-CoV-2 viral load through Day 8. Part B: The primary objective of this Part is to demonstrate superiority of ensovibep, compared to placebo, in reducing the occurrence of hospitalizations (≥ 24 hours of acute care) and/or emergency room visits related to COVID-19 or death from any cause up to Day 29. Secondary objectives: Part A: The secondary objectives of this Part are: * To assess the effect of ensovibep, compared to placebo, in reducing the occurrence of hospitalizations (≥ 24 hours of acute care) and/or emergency room visits related to COVID-19 or death from any cause up to Day 29 * To assess the effect of ensovibep, compared to placebo, in reducing COVID-19 symptoms through Day 29 * To evaluate safety and tolerability of ensovibep * To characterize the pharmacokinetics (PK) of ensovibep Part B: The secondary objectives of this Part are: * To assess the effect of ensovibep, compared to placebo, in reducing SARS-CoV-2 viral load through Day 8 * To assess the effect of ensovibep, compared to placebo, in reducing COVID-19 symptoms up to Day 29 * To evaluate the immunogenicity of ensovibep during the study and its clinical relevance (PK, efficacy and safety) * To evaluate safety and tolerability of ensovibep Although Amendment 2 was created, modifications for this amendment are not reflected as it was never approved or implemented in the US. The study was conducted under Global Protocol Amendment 1, the last active version of the protocol.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

407

Conditions

COVID-19

Interventions

ensovibepDRUG

IV on day 1 only.

PlaceboDRUG

IV on day 1 only.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Part A Inclusion Criteria: 1. Men and women ≥ 18 years of age on the day of inclusion (no upper limit). 2. Presence of two or more of the following COVID-19 symptoms with an onset within 7 days of dosing: Feeling hot or feverish, cough, sore throat, low energy, or tiredness, headache, muscle or body aches, chills or shivering, and shortness of breath. 3. Positive test for SARS-CoV-2 in upper respiratory swab on the day of dosing (rapid antigen test). 4. Understand and agree to comply with the planned study procedures. 5. The patient or legally authorized representative give signed informed consent. Part A Exclusion Criteria: 1. Requiring hospitalization at time of screening, or at time of study drug administration. 2. Oxygen saturation (SpO2) ≤ 93% on room air at sea level or ratio of arterial oxygen partial pressure (PaO2 in mmHg) to fractional inspired oxygen (FiO2) \< 300, respiratory rate ≥ 30 per minute, and heart rate ≥ 125 per minute. In India, patients with a respiratory rate ≥ 24 per minute or with an oxygen saturation ≤ 93% on room air (SpO2) are not eligible. 3. Known allergies to any of the components used in the formulation of the ensovibep or placebo. 4. Suspected or proven serious, active bacterial, fungal, viral, or other infection (besides SARS-CoV-2) that in the opinion of the investigator could constitute a risk when taking intervention. 5. Any serious concomitant systemic disease, condition, or disorder that, in the opinion of the investigator, should preclude participation in this study. 6. Any co-morbidity requiring surgery within 7 days of dosing, or that is considered life-threatening within 29 days of dosing. 7. Prior or concurrent use of any medication for treatment of COVID-19, including antiviral agents, convalescent serum, or anti-viral antibodies. Purely symptomatic therapies (e.g., over-the-counter \[OTC\] cough medications, acetaminophen, and nonsteroidal anti-inflammatory drugs \[NSAIDs\]) are permitted. Prior vaccination for COVID-19 is permitted. 8. Are concurrently enrolled or were enrolled within the last 30 days or within 5 half-lives (whichever is longer) in any other type of medical research judged not to be scientifically or medically compatible with this study. 9. Are pregnant or breast feeding. 10. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception at the time of dosing and for 11 weeks after dosing of study drug. Highly effective contraception methods include: 1. Total abstinence (when this is in line with the preferred and usual lifestyle of the patient). Periodic abstinence (i.e., calendar, ovulation, symptothermal, and postovulation methods) and withdrawal are not acceptable methods of contraception. 2. Female sterilization (have had bilateral surgical oophorectomy \[with or without hysterectomy\], total hysterectomy, or bilateral tubal ligation at least 6 weeks before taking study treatment). In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment. 3. Male sterilization (at least 6 months prior to screening). The vasectomized male partner should be the sole partner for that patient. 4. Use of oral, injected, or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal contraception that have comparable efficacy (failure rate \< 1%), for example hormone vaginal ring or transdermal hormone contraception. In case of use of oral contraception, women should have been stable on the same pill for a minimum of 3 months before taking study treatment. If local regulations deviate from the contraception methods listed above to prevent pregnancy, local regulations apply and will be described in the informed consent form (ICF). 11. Patients in the USA who are at high risk of progression to severe COVID-19 illness or hospitalization must not be enrolled in Part A of this study as a placebo-controlled study may not be appropriate in this patient population due to the availability of anti-viral mAbs under EUA in the USA.

Locations (48)

Outcomes

Primary Outcomes

Part A: Time-Weighted Change From Baseline in Log10 Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Viral Load Through Day 8

The SARS-CoV-2 viral load was measured by means of a nasopharyngeal swab, followed by quantitative reverse transcription-polymerase chain reaction assay at a central laboratory. The multiple comparison procedure-modeling methodology was used. Time-weighted change from baseline was used as viral loads were measured at multiple time points.

Time frame: Baseline (Day 1) and Days 3, 5 and 8

Part B: Percentage of Participants With Hospitalizations and/or Emergency Room (ER) Visits Related to COVID-19 or Death From Any Cause

Percentage of participants experiencing hospitalizations \[\>= 24 hour (h) of acute care\] and/or ER visits related to COVID-19 or death from any cause up to Day 29.

Time frame: Up to Day 29

Secondary Outcomes

Part A: Percentage of Participants With Hospitalizations and/or ER Visits Related to COVID-19 or Death From Any Cause

Percentage of participants experiencing hospitalizations (\>= 24 h of acute care) and/or ER visits related to COVID-19 or death from any cause up to Day 29 were presented along with relative risk to placebo.

Time frame: Up to Day 29

Part A: Time to Sustained Clinical Recovery

Sustained clinical recovery was defined as follows; 1. All symptoms from the modified Food and Drug Administration (FDA) COVID-19 questionnaire scored as moderate or severe at baseline were subsequently scored as mild or absent, and 2. All symptoms from the modified FDA COVID-19 questionnaire scored as mild or absent at baseline were subsequently scored as absent, with no subsequent worsening, up to Day 29.

Time frame: Up to Day 29

Part A: Observed Maximum Serum Concentration (Cmax) of Total and Free Ensovibep

Blood samples were collected to determine the Cmax of free ensovibep (ensovibep not bound to target) and total ensovibep (sum of ensovibep not bound to and bound to target) concentrations in serum.

Data from ClinicalTrials.gov

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Jasper Summit Research, LLC

Jasper, Alabama, United States

Benchmark Southern California

Colton, California, United States

Ascada Research

Fullerton, California, United States

Pacific Neuropsychiatric Specialists

Mission Viejo, California, United States

Providence Family Medical Center

Redondo Beach, California, United States

Future Innovative Treatments

Colorado Springs, Colorado, United States

Boward Infectious Disease and Primary Care

Margate, Florida, United States

Suncoast Research Group, LLC

Miami, Florida, United States

Life Spring Research Foundation

Miami, Florida, United States

Bio-Medical Research, LLC

Miami, Florida, United States

...and 38 more locations

Time frame: Data was summarized from pre-dose and at 15 minutes and 90 minutes after end of study drug infusion on Day 1, and at Days 3, 8, 15, 29, 61 and 91

Part A: Area Under the Concentration-Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Total and Free Ensovibep

Blood samples were collected to determine the AUClast of free ensovibep (ensovibep not bound to target) and total ensovibep (sum of ensovibep not bound to and bound to target) concentrations in serum.

Time frame: Data was summarized from pre-dose and at 15 minutes and 90 minutes after end of study drug infusion on Day 1, and at Days 3, 8, 15, 29, 61 and 91

Part A: Area Under the Concentration-Time Curve From Time Zero to 48 Hours (AUC 0-48h) of Total and Free Ensovibep

Blood samples were collected to determine the AUC 0-48h of free ensovibep (ensovibep not bound to target) and total ensovibep (sum of ensovibep not bound to and bound to target) concentrations in serum.

Time frame: Data was summarized from pre-dose and at 15 minutes and 90 minutes after end of study drug infusion on Day 1, and at Day 3

Part A: Area Under the Concentration-Time Curve From Time Zero to 168 Hours (AUC 0-168h) of Total and Free Ensovibep

Blood samples were collected to determine the AUC 0-168h of free ensovibep (ensovibep not bound to target) and total ensovibep (sum of ensovibep not bound to and bound to target) concentrations in serum.

Time frame: Data was summarized from pre-dose and at 15 minutes and 90 minutes after end of study drug infusion on Day 1, and at Days 3 and 8

Part A: Area Under the Concentration-Time Curve From Time Zero to 336 Hours (AUC 0-336h) of Total and Free Ensovibep

Blood samples were collected to determine the AUC 0-336h of free ensovibep (ensovibep not bound to target) and total ensovibep (sum of ensovibep not bound to and bound to target) concentrations in serum.

Time frame: Data was summarized from pre-dose and at 15 minutes and 90 minutes after end of study drug infusion on Day 1, and at Days 3, 8 and 15

Part A: Area Under the Concentration-Time Curve From Time Zero to Infinity (AUCinfinity) of Total and Free Ensovibep

Blood samples were collected to determine the AUCinfinity of free ensovibep (ensovibep not bound to target) and total ensovibep (sum of ensovibep not bound to and bound to target) concentrations in serum.

Time frame: Data was summarized from pre-dose and at 15 minutes and 90 minutes after end of study drug infusion on Day 1, and at Days 3, 8, 15, 29, 61 and 91

Part A: Time to Reach the Maximum Concentration (Tmax) of Total and Free Ensovibep

Blood samples were collected to determine the Tmax of free ensovibep (ensovibep not bound to target) and total ensovibep (sum of ensovibep not bound to and bound to target) concentrations in serum.

Time frame: Data was summarized from pre-dose and at 15 minutes and 90 minutes after end of study drug infusion on Day 1, and at Days 3, 8, 15, 29, 61 and 91

Part A: Apparent Total Body Clearance (CL) of Total and Free Ensovibep

Blood samples were collected to determine the CL of free ensovibep (ensovibep not bound to target) and total ensovibep (sum of ensovibep not bound to and bound to target) concentrations in serum.

Time frame: Data was summarized from pre-dose and at 15 minutes and 90 minutes after end of study drug infusion on Day 1, and at Days 3, 8, 15, 29, 61 and 91

Part A: Terminal Elimination Rate Constant (Lambda z) of Total and Free Ensovibep

Blood samples were collected to determine the lambda z of free ensovibep (ensovibep not bound to target) and total ensovibep (sum of ensovibep not bound to and bound to target) concentrations in serum.

Time frame: Data was summarized from pre-dose and at 15 minutes and 90 minutes after end of study drug infusion on Day 1, and at Days 3, 8, 15, 29, 61 and 91

Part A: Terminal Elimination Half-Life (T1/2) of Total and Free Ensovibep

Blood samples were collected to determine the T1/2 of free ensovibep (ensovibep not bound to target) and total ensovibep (sum of ensovibep not bound to and bound to target) concentrations in serum.

Time frame: Data was summarized from pre-dose and at 15 minutes and 90 minutes after end of study drug infusion on Day 1, and at Days 3, 8, 15, 29, 61 and 91

Part A: Apparent Volume of Distribution (Vz) of Total and Free Ensovibep

Blood samples were collected to determine the Vz of free ensovibep (ensovibep not bound to target) and total ensovibep (sum of ensovibep not bound to and bound to target) concentrations in serum.

Time frame: Data was summarized from pre-dose and at 15 minutes and 90 minutes after end of study drug infusion on Day 1, and at Days 3, 8, 15, 29, 61 and 91

Part B: Change From Baseline in Log10 SARS-CoV-2 Viral Load Through Day 8

Time frame: Baseline (Day 1) and Days 3, 5 and 8

Part B: Time to Sustained Clinical Recovery

Sustained clinical recovery was defined as follows; 1. All symptoms from the modified FDA COVID-19 questionnaire scored as moderate or severe at baseline were subsequently scored as mild or absent, and 2. All symptoms from the modified FDA COVID-19 questionnaire scored as mild or absent at baseline were subsequently scored as absent, with no subsequent worsening, up to Day 29.

Time frame: Up to Day 29

Part B: Percentage of Participants With Treatment-Emergent Anti-Drug Antibody (ADA) Response to Ensovibep

Treatment-emergent ADA is defined as any participant with a 1. 2-fold (1 dilution) increase in titer than the minimum required dilution if no ADAs were detected at baseline (treatment-induced ADA); or, 2. 4-fold (2 dilutions) increase in titer compared with baseline if ADAs were detected at baseline (treatment-boosted ADA).

Time frame: Pre-dose on Day 1 and Days 15, 29, 61 and 91 postdose of Ensovibep