Clinical trial NCT05293249: dMAbs for Prevention of COVID-19
Official title: A Phase 1, Open-Label, Single Center, Dose Escalation Study of the Safety and Pharmacokinetics of mAb AZD5396 and mAb AZD8076 Delivered as dMAbs in Healthy Adults
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Healthy Volunteers
Lead sponsor: University of Pennsylvania
Sponsor class: OTHER
Collaborators: name: The Wistar Institute
name: AstraZeneca
name: Inovio Pharmaceuticals
First posted: 2022-03-24
Enrollment: 61
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Dose escalation
Primary purpose: PREVENTION

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 2-dose regimen (Days 0 and 3) or a 4-dose regimen (Days 0, 3, 28 and 31) 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.

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 Cohorts B, C and E. Because cohorts D, F \& G are a similar or lower dose and the safety profile would have been already established in previous cohorts, the 14-day waiting periods will not apply to Cohorts D, F or G.

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.

Eligibility 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 31, 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 one of the following:

   1. use medically effective contraception (oral contraception, barrier methods, spermicide, etc.)
   2. have a partner who is sterile from enrollment to 6 months following the last injection
   3. 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 one of the following:

   1. use a barrier method of contraception during the study and continue its use for at least 6 months following the last injection
   2. 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 14 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 poorly-controlled diabetes (HbA1C \> 7), poorly-controlled hypertension (BP \> 140/95 repeatedly), 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.

Primary outcomes:
measure: Frequency and nature of injection site reaction
timeFrame: 7 days after administration of the investigational products
measure: Frequency and nature of systemic reactions
timeFrame: 7 days after administration of the investigational products
measure: Frequency and nature of Serious Adverse Events
timeFrame: 72 Weeks after administration of the investigational products
measure: Evaluation of the pain experienced by the participant
timeFrame: Immediately after EP, 5 minutes after EP and 10 minutes after EP
measure: Evaluation of laboratory related adverse events
timeFrame: Up to 7 days after administration of the investigational product
measure: Serum concentration of dMAb AZD5396 nm/mL.
timeFrame: Up to 72 Weeks after administration of the investigational products
measure: Serum concentration of dMAb AZD8076 nm/mL.
timeFrame: Up to 72 Weeks after administration of the investigational products
Secondary outcomes:
Other outcomes:
Locations:
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
Study officials:
affiliation: University of Pennsylvania
name: Pablo Tebas, MD
role: PRINCIPAL_INVESTIGATOR
References: