Precis_-_Clinical_Monitoring.pdf

Appendix – A

VRC 207 Study: A Phase 1/1b, Open-Label, Dose-Escalation Clinical Trial to Evaluate the Safety, Tolerability and Immunogenicity of the Ebola Chimpanzee Adenovirus Vector Vaccines VRC-EBOADC069-00-VP (cAd3-EBO), and VRC-EBOADC076-00-VP

(cAd3-EBOZ), in Healthy Adults

Study Design: This is a Phase 1/1b, open-label study to examine safety, tolerability and immunogenicity of investigational Ebola vaccines in healthy adults. Part 1 is a Phase 1 dose escalation of the cAd3-EBO vaccine that encodes wild type (WT) glycoproteins (GP) from Zaire and Sudan strains of Ebolavirus. Part 2 is a Phase 1b further evaluation of the cAd3-EBO vaccine at the highest dose and evaluation of the Zaire component, which will be provided as a vaccine designated “cAd3-EBOZ.” The hypotheses are that the study vaccines, cAd3-EBO and cAd3-EBOZ, will be safe and will elicit immune responses to Ebola GP. The primary objectives are to evaluate the safety and tolerability of the study vaccines administered as single intramuscular (IM) injections at two dose levels. The secondary objectives are related to evaluation of the immunogenicity.

Product Description: VRC-EBOADC069-00-VP (cAd3-EBO) is composed of two recombinant cAd3 vectors in a 1:1 ratio that express Ebola WT GPs from Zaire and Sudan strains. It is formulated at 2 x 1011 PU/mL.

VRC-EBOADC076-00-VP (cAd3-EBOZ) is composed of a cAd3 vector that expresses Ebola WT GP from the Zaire strain. It is formulated at 1 x 1011 PU/mL.

VRC-DILADC065-00-VP (diluent) is the formulation buffer used for vaccine production and will be used when needed to prepare the correct dosage of cAd3-EBO and cAd3-EBOZ.

Subjects: Part 1: Healthy adult volunteers, 18 to 50 years old;

Part 2: Healthy adult volunteers, 18 to 65 years old.

Study Plan: Part 1: 20 subjects will be enrolled, with 10 in each of the two dosage groups for cAd3- EBO. The dose escalation plan includes daily review of any new safety data by a study clinician, weekly review of safety data by the protocol team and a staged enrollment plan with required interim safety reviews before proceeding to the next step. The study plan includes no more than one enrollment per day for the first 3 vaccinated subjects in each group. After at least 3 days of follow-up, an interim safety review will occur before enrollment of additional subjects into the group. When there are at least 2 weeks of follow-up safety data for the first 3 vaccinated subjects in Group 1, an interim safety review will occur before proceeding to the next dose level.

Part 2: About 130 subjects will be enrolled as shown in the Schema table.

Group 3 is open only to subjects who received Ebola DNA WT vaccine in protocol VRC 206 to receive cAd3-EBO as a booster vaccine at the 2 x 1011 PU dose.

Group 4 is for randomization of subjects to two dosage groups of cAd3-EBOZ. Group 5 is for further evaluation of the cAd3-EBO vaccine at the 2 x 1011 PU dose.

VRC 207 Schema

Group Description Subjects Day 0

Part 1: Phase 1 Dose Escalation of cAd3-EBO

1 Low dose cAd3-EBO 10 cAd3-EBO at 2x1010 PU IM

2 High dose cAd3-EBO 10 cAd3-EBO at 2x1011 PU IM

Part 2: Phase 1b Dose Evaluation of cAd3-EBOZ and Further Evaluation of cAd3-EBO

3 *Boost DNA WT EBO 10 cAd3-EBO at 2x1011 PU IM

4a Randomize to low dose and high dose cAd3-

EBOZ

10 cAd3-EBOZ at 1x1010 PU IM

4b 10 cAd3-EBOZ at 1x1011 PU IM

5 Further evaluate cAd3-EBO 100 cAd3-EBO at 2x1011 PU IM

*150

All injections: administered in 1 mL volume.

* If fewer than 10 subjects from VRC 206 enroll into Group 3; unused slots may be reallocated to Group 5.

Study

Duration: Subjects will be evaluated by various clinic visits over 48 weeks as detailed in the table below.

Sample Schedule

VRC 207 Schedule of Evaluations Visit 01 02 02A 02B 02C 02D 03 04 05 06 07 Week of Study -8 to 0 W 0 W 1 W 1 W1 W2 W4 W 8 W 16 W 24 W 48 1Day of Study -56 to 0 D 0 D 1 D 3 D 7 D14 D 28 D 56 D 112 D 168 D 336 Clinical Evaluations Tube Screening Consent X VRC 207 AoU, Informed Consent X Physical exam and weight at screen; Vital signs, targeted exam

X X X X X X X X X X

Medical history for eligibility at screen; interim history other visits

X X X X X X X X X X 2 Study Vaccination X Begin 7-Day Diary Card X Telephone contact; clinic visit if X Counseling on pregnancy prevention X X X X X

CBC EDTA 3 3 3 3 3 3 3

3 Pregnancy test: urine (or serum) X X X X Creatinine and ALT GLT 4 4 4 4 4 4

HIV X

4PT and PTT Blue 4 4 4 4 4 5 HLA type EDTA 20 Research Immunology Antibody assays and serum storage SST 24 24 16 16 16 24 24 24 24 24 PBMC and plasma for storage EDTA 60 80 60 40 80 60 60 80 80 Intracellular RNA PAXgen 3 6 6 Daily Volume (mL) 95 118 33 82 67 115 111 84 107 104 Max. Cumulative Volume (mL) 95 213 246 328 395 510 621 705 812 916

1 Screening Consent: Most screening evaluations must be no more than 56 days prior to Day 0 to be used for eligibility (pregnancy test from Day 0 must be used for eligibility).

If clinical assessment on Day 0 suggests significant changes may have occurred since screening, then physical examination & laboratory studies done on Day 0 are used for eligibility. Day 0=day of enrollment and vaccine injection. Day 0 evaluations prior to first injection are the baseline for assessing adverse events subsequently.

2 Complete post vaccination blood pressure, pulse and injection site assessment after the study injection (target to complete this within the interval 15 to 60 minutes post- vaccination). Subjects in Groups 1 and 2 must remain in the clinic for 3 hours after injection; subsequent subjects must remain in the clinic for at least 1 hour after injection. 3 Negative pregnancy test results must be confirmed for women of reproductive potential prior to administering the vaccine injection.

4 Use 4.5 mL Blue top citrate tube; 3 mL minimum needs to be collected for accuracy of results. Additional tests may be needed if results are not in range.

5 HLA type blood sample is collected once at any timepoint in the study and is shown as a Visit 04 evaluation for convenience; however, if HLA type is already available in the medical record it does not need to be repeated. HLA type may also be obtained from a frozen sample.

Visit windows: 02A (+1 day); 02B (+2 days); 02C (+3 days); Visit 02D (±3 days); Visits 03 and 04 (±7 days); Visits 05, 06 and 07 (±14 days).

*The volume of research blood drawn may be greater than shown on the SOE; cumulative draw cannot exceed allowance of Med.Admin. Series 95-9 or about 15 tubes per visit.