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

• ClinicalTrials.gov Identifier: NCT04828161
• Recruitment Status: Terminated
• First Posted: April 1, 2021
• Results First Posted: January 18, 2023
• Last Update Posted: January 18, 2023
• Sponsor: Novartis Pharmaceuticals
• Collaborator: Molecular Partners AG
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
COVID-19	Drug: ensovibep; Drug: Placebo	Phase 2; Phase 3

Detailed Description:

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 407 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment

Intervention Model Description

• Parallel: participants are assigned to one of two or more groups in parallel for the duration of the study.
• 4 Arms under Phase 2 and 2 Arms under Phase 3

• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description

• Double Blind: two or more parties are unaware of the intervention assignment
• Masked roles are: Subject, Caregiver, Investigator or Outcomes Assessor.

• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Placebo-controlled, Multicenter Study of Ensovibep (MP0420) in Ambulatory Adult Patients With Symptomatic COVID-19 - The "EMPATHY" Trial
• Actual Study Start Date: May 10, 2021
• Actual Primary Completion Date: November 18, 2021
• Actual Study Completion Date: January 27, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Phase 2 / Part A, ensovibep active treatment arm 1; Phase 2 / Part A: ensovibep active treatment arm 1	Drug: ensovibep; IV on day 1 only.; Other Name: MP0420
Experimental: Phase 2 / Part A, ensovibep active treatment arm 2; Phase 2 / Part A: ensovibep active treatment arm 2	Drug: ensovibep; IV on day 1 only.; Other Name: MP0420
Experimental: Phase 2 / Part A, ensovibep active treatment arm 3; Phase 2 / Part A: ensovibep active treatment arm 3	Drug: ensovibep; IV on day 1 only.; Other Name: MP0420
Placebo Comparator: Phase 2 / Part A, Placebo; Phase 2 / Part A: Placebo	Drug: Placebo; IV on day 1 only.
Experimental: Phase 3/ Part B, ensovibep active treatment arm 4; Phase 3/ Part B: ensovibep active treatment. Part B was not initiated.	Drug: ensovibep; IV on day 1 only.; Other Name: MP0420
Placebo Comparator: Phase 3/ Part B, Placebo arm; Phase 3/ Part B: Placebo. Part B was not initiated.	Drug: Placebo; IV on day 1 only.

Outcome Measures

Primary Outcome Measures :

1. Part A: Time-Weighted Change From Baseline in Log10 Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Viral Load Through Day 8 [ Time Frame: Baseline (Day 1) and Days 3, 5 and 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.
2. Part B: Percentage of Participants With Hospitalizations and/or Emergency Room (ER) Visits Related to COVID-19 or Death From Any Cause [ Time Frame: Up to Day 29 ]
   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.

Secondary Outcome Measures :

1. Part A: Percentage of Participants With Hospitalizations and/or ER Visits Related to COVID-19 or Death From Any Cause [ Time Frame: Up to Day 29 ]
   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.
2. Part A: Time to Sustained Clinical Recovery [ Time Frame: Up to Day 29 ]

   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.
3. Part A: Observed Maximum Serum Concentration (Cmax) of Total and Free Ensovibep [ 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 ]
   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.
4. 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 [ 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 ]
   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.
5. Part A: Area Under the Concentration-Time Curve From Time Zero to 48 Hours (AUC 0-48h) of Total and Free Ensovibep [ 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 ]
   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.
6. Part A: Area Under the Concentration-Time Curve From Time Zero to 168 Hours (AUC 0-168h) of Total and Free Ensovibep [ 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 ]
   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.
7. Part A: Area Under the Concentration-Time Curve From Time Zero to 336 Hours (AUC 0-336h) of Total and Free Ensovibep [ 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 ]
   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.
8. Part A: Area Under the Concentration-Time Curve From Time Zero to Infinity (AUCinfinity) of Total and Free Ensovibep [ 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 ]
   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.
9. Part A: Time to Reach the Maximum Concentration (Tmax) of Total and Free Ensovibep [ 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 ]
   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.
10. Part A: Apparent Total Body Clearance (CL) of Total and Free Ensovibep [ 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 ]
    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.
11. Part A: Terminal Elimination Rate Constant (Lambda z) of Total and Free Ensovibep [ 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 ]
    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.
12. Part A: Terminal Elimination Half-Life (T1/2) of Total and Free Ensovibep [ 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 ]
    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.
13. Part A: Apparent Volume of Distribution (Vz) of Total and Free Ensovibep [ 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 ]
    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.
14. 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 ]
    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.
15. Part B: Time to Sustained Clinical Recovery [ Time Frame: Up to Day 29 ]

    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.
16. Part B: Percentage of Participants With Treatment-Emergent Anti-Drug Antibody (ADA) Response to Ensovibep [ Time Frame: Pre-dose on Day 1 and Days 15, 29, 61 and 91 postdose of 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).

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

United States, Alabama

Jasper Summit Research, LLC

Jasper, Alabama, United States, 35501

United States, California

Benchmark Southern California

Colton, California, United States, 92324

Ascada Research

Fullerton, California, United States, 92835

Pacific Neuropsychiatric Specialists

Mission Viejo, California, United States, 92691

Providence Family Medical Center

Redondo Beach, California, United States, 90277

United States, Colorado

Future Innovative Treatments

Colorado Springs, Colorado, United States, 80907

United States, Florida

Boward Infectious Disease and Primary Care

Margate, Florida, United States, 33063

Panax Clinical Research, LLC

Miami Lakes, Florida, United States, 33014

Suncoast Research Group, LLC

Miami, Florida, United States, 33135

Life Spring Research Foundation

Miami, Florida, United States, 33155

Bio-Medical Research, LLC

Miami, Florida, United States, 33184

AdventHealth Tampa

Tampa, Florida, United States, 33613

Palm Beach Research Center

West Palm Beach, Florida, United States, 33409

United States, Georgia

Gwinnett Research Institute

Buford, Georgia, United States, 30519

IACT Health

Columbus, Georgia, United States, 31904

United States, Illinois

Great Lakes Clinical Trials

Chicago, Illinois, United States, 60640

United States, Maryland

Centennial Medical Group - Research Department

Elkridge, Maryland, United States, 21075

United States, Missouri

Jefferson City Medical Group

Jefferson City, Missouri, United States, 65109

United States, North Carolina

Monroe Biomedical Research

Monroe, North Carolina, United States, 28112

Wilmington Health

Wilmington, North Carolina, United States, 28412

United States, South Carolina

VitaLink Research

Greenville, South Carolina, United States, 29615

Clinical Research of Rock Hill

Rock Hill, South Carolina, United States, 29732

United States, Texas

Fairway Medical Clinic

Houston, Texas, United States, 77087

1960 Family Practice, PA

Houston, Texas, United States, 77090

Zion Urgent Care Clinic

Katy, Texas, United States, 77494

Family Practice Center

McAllen, Texas, United States, 78501

Epic Medical Research

Red Oak, Texas, United States, 75154

Hungary

Debreceni Egyetem

Debrecen, Hungary, 4031

India

King George Hospital

Visakhapatnam, Andhra Pradesh, India, 530002

BAPS Pramukhswami Hospital

Surat, Gujarat, India, 395009

Durgabai Deshmukh Hospital & Research Centre

Vidyanagar, Hyderabad, India, 500044

Shetty's Hospital

Bengaluru, Karnataka, India, 560068

Government Medical College

Aurangabad, Maharashtra, India, 431001

Grant Medical College & Sir J. J. Group of Hospitals

Mumbai, Maharashtra, India, 400008

Government Medical College and Hospital

Nagpur, Maharashtra, India, 440003

All India Institute of Medical Sciences - Nagpur

Nagpur, Maharashtra, India, 441108

VHS-Infectious Disease Medical Centre

Chennai, Tamil Nadu, India, 600113

St. Theresa's Hospital

Hyderabad, Telangana, India, 500018

Netherlands

UMC Utrecht

Utrecht, Netherlands, 3584 CW

South Africa

FARMOVS (Pty) Ltd

Bloemfontein, Free State, South Africa, 9301

Sandton Medical Research Centre

Sandton, Gauteng, South Africa, 2196

George Provincial Hospital

George, Western Cape, South Africa, 6529

Dr JM Engelbrecht Trial Site

Somerset West, Western Cape, South Africa, 7130

Enhancing Care Foundation

Durban, South Africa, 4052

Clinresco Centres (Pty) Ltd

Kempton Park, South Africa, 1619

DJW Navorsing

Krugersdorp, South Africa, 1739

Jongaie Research

Pretoria, South Africa, 183

Wits Clinical Research

Soweto, South Africa, 2013

Sponsors and Collaborators

Novartis Pharmaceuticals

Molecular Partners AG

  Study Documents (Full-Text)

Documents provided by Novartis ( Novartis Pharmaceuticals ):

Study Protocol  [PDF] October 19, 2021

Statistical Analysis Plan  [PDF] December 7, 2021

More Information

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT04828161
• Other Study ID Numbers: MP0420-CP302; 2021-000890-10 ( EudraCT Number ); CSKO136A12201J ( Other Identifier: Novartis Pharmaceuticals )
• First Posted: April 1, 2021
• Results First Posted: January 18, 2023
• Last Update Posted: January 18, 2023
• Last Verified: December 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes

Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on https://www.clinicalstudydatarequest.com/.

• URL: https://www.clinicalstudydatarequest.com/

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

ensovibep; COVID-19 treatment, symptom reduction, viral load reduction,; EMPATHY; SARS-CoV-2; designed ankyrin repeat protein (DARPin®); angiotensin-converting enzyme 2 (ACE2)

Additional relevant MeSH terms:

COVID-19; Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases