dMAbs for Prevention of COVID-19

• ClinicalTrials.gov Identifier: NCT05293249
• Recruitment Status: Active, not recruiting
• First Posted: March 24, 2022
• Last Update Posted: April 21, 2023
• Sponsor: Pablo Tebas
• Collaborators: The Wistar Institute; AstraZeneca; Inovio Pharmaceuticals
• Information provided by (Responsible Party): Pablo Tebas, University of Pennsylvania

Study Description

Brief Summary:

This is a Phase 1, open-label, single center, dose escalation study to evaluate the safety, tolerability and pharmacokinetic profile of mAb AZD5396 and mAb AZD8076 following delivery of optimized dMAb AZD5396 and dMAb AZD8076 with Hylenex® Recombinant, administered by intramuscular injection (IM) followed immediately by electroporation (EP) using the CELLECTRA® 2000 with Side Port needle device, in a 1 and 2-dose regimen (Days 0 and 3) in healthy adults The hypothesis is that the administration of dMAb AZD5396 and dMAb AZD8076 will be safe and associated with expression of mAb AZD5396 and mAb AZD8076 in serum.

Condition or disease	Intervention/treatment	Phase
Healthy Volunteers	Combination Product: dMAb AZD5396; Combination Product: dMAb AZD8076; Combination Product: Electroporation device; Drug: Hylenex; Drug: Methylprednisolone	Phase 1

Detailed Description:

The study will apply a single ascending dose (SAD) modified 3+3 design. Participants will be enrolled sequentially beginning with Cohort A1. The first participant in cohort A1 will be dosed on Day 0. If no stopping event (DLT) is observed after 14 days of the initial dose, the remaining two participants in that cohort will be dosed. If there are 0 DLT events after 14 days of the initial dosing of the third subject, enrollment will be completed, and then cohort A2 will open. Same process will be followed for each one of the next cohorts (cohorts B, C and D will have 6 participants in each).

If one dose limiting toxicity (DLT) is observed in the first three participants enrolled in any cohort, an ad hoc DSMB will review the event and make a decision if the study should continue. If the DSMB agrees that the study should continue, the remaining participants will be enrolled in the cohort and dosed, but the next cohort will not open until the 28-day period of safety is completed. However, if any additional DLT occurs (i.e., >1 DLT in 6 total participants in a given cohort), then that dose will be deemed not tolerated

The following Investigational product administration- and/or EP- related adverse events are defined as DLTs:

• Grade 3 or greater local injection site erythema, swelling, and/or induration recorded ≥ 1 hour after Investigational product administration
• Pain or tenderness at the injection site that requires overnight hospitalization despite proper use of non-narcotic analgesics.
• Grade 3 or greater systemic symptoms assessed by the Principal Investigator as related to Investigational product administration.
• Grade 3 or greater clinically significant laboratory abnormalities assessed by the Principal Investigator as related to Investigational product administration.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 26 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Intervention Model Description: Dose escalation
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: A Phase 1, Open-Label, Single Center, Dose Escalation Study of the Safety and Pharmacokinetics of dMAb AZD5396 and dMAb AZD8076 Delivered as dMAbs in Healthy Adults
• Actual Study Start Date: May 19, 2022
• Estimated Primary Completion Date: September 2024
• Estimated Study Completion Date: September 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Cohort A1 - 1x 0.5 mg; Participants (n=3) will be administered 0.5 mg of dMAb AZD5396 and 0.5 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) on D0, for a total dose of 0.5 mg of each plasmid.	Combination Product: dMAb AZD5396; Participants will receive one injection of dMAb AZD5396 with Hylenex into the arm (deltoid)/leg (quadriceps) region followed by EP.; Combination Product: dMAb AZD8076; Participants will receive one injection of dMAb AZD8076 with Hylenex into the arm (deltoid)/leg (quadriceps) region followed by EP.; Combination Product: Electroporation device; The device will be used to perform electroporation (EP) on each subject immediately after being dosed with dMAb AZD5396 and dMAb AZD8076.; Drug: Hylenex; Hylenex® recombinant will be used for dMAb AZD5396 and dMAb AZD8076 dose preparation at the clinical site.
Experimental: Cohort A2 - 1x 1 mg; Participants (n=3) will be administered 1 mg of dMAb AZD5396 and 1 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) on D0, for a total dose of 1 mg of each plasmid.	Combination Product: dMAb AZD5396; Participants will receive one injection of dMAb AZD5396 with Hylenex into the arm (deltoid)/leg (quadriceps) region followed by EP.; Combination Product: dMAb AZD8076; Participants will receive one injection of dMAb AZD8076 with Hylenex into the arm (deltoid)/leg (quadriceps) region followed by EP.; Combination Product: Electroporation device; The device will be used to perform electroporation (EP) on each subject immediately after being dosed with dMAb AZD5396 and dMAb AZD8076.; Drug: Hylenex; Hylenex® recombinant will be used for dMAb AZD5396 and dMAb AZD8076 dose preparation at the clinical site.
Experimental: Cohort B - 2x 0.5 mg; Participants (n=6) will be administered 0.5 mg of dMAb AZD5396 and 0.5 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) on D0 and D3, for a total dose of 1 mg of each plasmid.	Combination Product: dMAb AZD5396; Participants will receive one injection of dMAb AZD5396 with Hylenex into the arm (deltoid)/leg (quadriceps) region followed by EP.; Combination Product: dMAb AZD8076; Participants will receive one injection of dMAb AZD8076 with Hylenex into the arm (deltoid)/leg (quadriceps) region followed by EP.; Combination Product: Electroporation device; The device will be used to perform electroporation (EP) on each subject immediately after being dosed with dMAb AZD5396 and dMAb AZD8076.; Drug: Hylenex; Hylenex® recombinant will be used for dMAb AZD5396 and dMAb AZD8076 dose preparation at the clinical site.
Experimental: Cohort C - 2x 1 mg; Participants (n=6) will be administered 1mg of dMAb AZD5396 and 1 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) on D0 and D3, for a total dose of 2 mg of each plasmid.	Combination Product: dMAb AZD5396; Participants will receive one injection of dMAb AZD5396 with Hylenex into the arm (deltoid)/leg (quadriceps) region followed by EP.; Combination Product: dMAb AZD8076; Participants will receive one injection of dMAb AZD8076 with Hylenex into the arm (deltoid)/leg (quadriceps) region followed by EP.; Combination Product: Electroporation device; The device will be used to perform electroporation (EP) on each subject immediately after being dosed with dMAb AZD5396 and dMAb AZD8076.; Drug: Hylenex; Hylenex® recombinant will be used for dMAb AZD5396 and dMAb AZD8076 dose preparation at the clinical site.
Experimental: Cohort D - 2x 1 mg plus methylprednisolone; Participants (n=6) will be administered 1 mg of dMAb AZD5396 and 1 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) on D0 and D3, for a total dose of 2 mg of each plasmid. On D0, after completing the administration of the dMAb AZD5396 and dMAb AZD8076, the participants will receive in addition a single injection of 120 mg of methylprednisolone.	Combination Product: dMAb AZD5396; Participants will receive one injection of dMAb AZD5396 with Hylenex into the arm (deltoid)/leg (quadriceps) region followed by EP.; Combination Product: dMAb AZD8076; Participants will receive one injection of dMAb AZD8076 with Hylenex into the arm (deltoid)/leg (quadriceps) region followed by EP.; Combination Product: Electroporation device; The device will be used to perform electroporation (EP) on each subject immediately after being dosed with dMAb AZD5396 and dMAb AZD8076.; Drug: Hylenex; Hylenex® recombinant will be used for dMAb AZD5396 and dMAb AZD8076 dose preparation at the clinical site.; Drug: Methylprednisolone; Participants in cohort D, after completing the administration of the dMAb AZD5396 and dMAb AZD8076, will receive in addition a single injection of 120 mg of methylprednisolone

Outcome Measures

Primary Outcome Measures :

1. Frequency and nature of injection site reaction [ Time Frame: 7 days after administration of the investigational products ]
   Injection site reactions occurring up to 7 days after administration of the investigational product
2. Frequency and nature of systemic reactions [ Time Frame: 7 days after administration of the investigational products ]
   Systemic reactions occurring up to 7 days after administration of the investigational product.
3. Frequency and nature of Serious Adverse Events [ Time Frame: 72 Weeks after administration of the investigational products ]
   SAE will be classified using the CTCAE v5 throughout the study
4. Evaluation of the pain experienced by the participant [ Time Frame: Immediately after EP, 5 minutes after EP and 10 minutes after EP ]
   Visual analogue scale (VAS). A VAS consists of a horizontal line, 10 cm in length, anchored by word descriptors at each end (no pain = 0 cm; worst pain = 10 cm). The VAS score is determined by measuring in centimeters from the left hand end of the line to the point that the patient marks. Absolute initial value and change over time will be described.
5. Evaluation of laboratory related adverse events [ Time Frame: Up to 7 days after administration of the investigational product ]
   Laboratory AEs will be assessed and graded in accordance with the "Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials", issued in September 2007.
6. Serum concentration of dMAb AZD5396 nm/mL. [ Time Frame: Up to 72 Weeks after administration of the investigational products ]
   The number and percentage of participants in which detection of monoclonal antibody dMAb AZD5396 in serum is achieved will be summarized with a point estimate and corresponding exact 90% Clopper- Pearson confidence interval. These will be summarized per time point within each cohort. We will also estimate the time to 50% decline from peak concentration.
7. Serum concentration of dMAb AZD8076 nm/mL. [ Time Frame: Up to 72 Weeks after administration of the investigational products ]
   The number and percentage of participants in which detection of monoclonal antibody dMAb AZD8076 in serum is achieved will be summarized with a point estimate and corresponding exact 90% Clopper- Pearson confidence interval. These will be summarized per time point within each cohort. We will also estimate the time to 50% decline from peak concentration.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 60 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria

1. Age 18-60 years.
2. Able to provide consent to participate and having signed an Informed Consent Form (ICF).
3. Able and willing to comply with all study procedures.
4. Body mass index (BMI) between 20 and 30, inclusive.
5. Screening laboratory must be within normal limits or have only Grade 0-1 findings.
6. Normal screening ECG or screening ECG with no clinically significant findings.
7. Women of child-bearing potential agree to use medically effective contraception (oral contraception, barrier methods, spermicide, etc.) or have a partner who is sterile from enrollment to 6 months following the last injection or have a partner who is medically unable to induce pregnancy. Abstinence is acceptable per Investigator discretion and as long as it is documented that the subject will use medically effective contraception when engaging in sexual activities and notifies the study team.
8. Sexually active men who are considered sexually fertile must agree to use either a barrier method of contraception during the study, and agree to continue the use for at least 6 months following the last injection, or have a partner who is permanently sterile or is medically unable to become pregnant.
9. No history of clinically significant immunosuppressive or autoimmune disease. Individuals with HIV infection who have been virologically suppressed for more than 1 year and with current CD4 cell count entry greater than 500 cells/ul will be allowed into the study.

Exclusion Criteria

1. Administration of an investigational compound either currently or within 6 months of first dose.
2. Administration of any vaccine within 4 weeks of first dose.
3. Administration of a SARS-CoV-2 vaccine in the last 90 days or plans to have any standard of care vaccines within 14 days form the last administration of study products.
4. Positive SARS-CoV-2 infection at screening visit.
5. Administration of any monoclonal or polyclonal antibody product within 4 weeks of the first dose.
6. Administration of any blood product within 3 months of first dose.
7. Co-morbid conditions including diabetes, hypertension, asthma, and any cardiovascular disease.
8. Pregnancy or breast feeding or plans to become pregnant during the course of the study.
9. Positive serologic test for hepatitis B surface antigen (HBsAg); or any potentially communicable infectious disease as determined by the Principal Investigator or Medical Director.
10. Positive serologic test for hepatitis C (exception: successful treatment with confirmation of sustained virologic response);
11. Baseline evidence of kidney disease as measured by creatinine greater than 1.5 mg/dL (CKD Stage II or greater);
12. Baseline screening lab with Grade 2 or higher abnormality, except for Grade 2 creatinine.
13. Chronic liver disease or cirrhosis.
14. Immunosuppressive illness including hematologic malignancy, history of solid organ or bone marrow transplantation.
15. Current or anticipated concomitant immunosuppressive therapy (inhaled, topical skin and/or eye drop-containing corticosteroids, low-dose methotrexate, or prednisone at a dose less than 10 mg/day or steroid dose-equivalent are not exclusionary).
16. Current or anticipated treatment with TNF-α inhibitors such as infliximab, adalimumab, etanercept.
17. Prior major surgery or any radiation therapy within 6 months of first dose.
18. Any pre-excitation syndromes, e.g., Wolff-Parkinson-White syndrome.
19. Presence of a cardiac pacemaker or automatic implantable cardioverter defibrillator (AICD)

20. Fewer than two acceptable sites available for IM injection and EP considering the deltoid and anterolateral quadriceps muscles. The following are unacceptable sites:

    1. Tattoos, keloids or hypertrophic scars located within 2 cm of intended administration site.
    2. Implantable-Cardioverter-defibrillator (ICD) or pacemaker (to prevent a life-threatening arrhythmia) that is located ipsilateral to the deltoid injection site (unless deemed acceptable by a cardiologist).
    3. Any metal implants or implantable medical device within the electroporation site.
21. Prisoner or participants who are compulsorily detained (involuntary incarceration) for treatment of either a physical or psychiatric illness.
22. Active drug or alcohol use or dependence that, in the opinion of the investigator, would interfere with adherence to study requirements or assessment of immunologic endpoints.
23. Not willing to allow storage and future use of samples for SARS-CoV-2 virus related research.
24. Any illness or condition that in the opinion of the investigator may affect the safety of the participant or the evaluation of any study endpoint.
25. Participants with known bleeding diatheses or that are using blood thinners for 30 days before study enrollment including warfarin, heparin, Clopidogrel, Apixaban (Eliquis), Dabigatran (Pradaxa), Edoxaban (Savaysa), Rivaroxaban (Xarelto). The use of low dose aspirin (81 mg daily) is acceptable.
26. Participants with concomitant intramuscular medications.
27. Known previous intolerance or contraindication to methylprednisolone (for participants to be enrolled in Cohort D).

Contacts and Locations

Locations

United States, Pennsylvania

University of Pennsylvania

Philadelphia, Pennsylvania, United States, 19104

Sponsors and Collaborators

Pablo Tebas

The Wistar Institute

AstraZeneca

Inovio Pharmaceuticals

Investigators

• Principal Investigator: Pablo Tebas, MD; University of Pennsylvania

More Information

• Responsible Party: Pablo Tebas, Professor of Medicine. University of Pennsylvania, University of Pennsylvania
• ClinicalTrials.gov Identifier: NCT05293249
• Other Study ID Numbers: 850355
• First Posted: March 24, 2022
• Last Update Posted: April 21, 2023
• Last Verified: November 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: Yes
• Device Product Not Approved or Cleared by U.S. FDA: Yes

Additional relevant MeSH terms:

Methylprednisolone; Methylprednisolone Acetate; Methylprednisolone Hemisuccinate; Prednisolone; Prednisolone acetate; Prednisolone hemisuccinate; Prednisolone phosphate; Anti-Inflammatory Agents; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Neuroprotective Agents; Protective Agents; Antineoplastic Agents, Hormonal; Antineoplastic Agents