Study to Evaluate the Safety, Tolerability, and Efficacy of Vesatolimod in Combination With Tenofovir Disoproxil Fumarate (TDF) in Adults With Chronic Hepatitis B (CHB) Infection Who Are Currently Not Being Treated
Sponsor
Gilead Sciences (Industry)
Overall Status
Completed
CT.gov ID
NCT02579382
Collaborator
(none)
192
21
4
41.7
9.1
0.2
Study Details
Study Description
Brief Summary
The primary objectives of this study are to evaluate the safety, tolerability, and efficacy of vesatolimod (formerly GS-9620) in adults with chronic hepatitis B (CHB) infection who are currently not being treated.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Study Design
Study Type:
Interventional
Actual Enrollment
:
192 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double (Participant, Investigator)
Primary Purpose:
Treatment
Official Title:
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Multi-center Study to Evaluate the Safety and Efficacy of GS-9620 in Combination With Tenofovir Disoproxil Fumarate (TDF) for the Treatment of Subjects With Chronic Hepatitis B and Who Are Currently Not on Treatment
Actual Study Start Date
:
Nov 10, 2015
Actual Primary Completion Date
:
Jan 16, 2017
Actual Study Completion Date
:
May 3, 2019
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Placebo Comparator: TDF + placebo Main Study Phase: Tenofovir disoproxil fumarate (TDF) 300 mg tablets orally once daily for up to 48 weeks + placebo administered orally once a week (every 7 days) for 12 doses. Optional Treatment Extension Phase: At Week 48 participants had the option to continue TDF 300 mg tablets orally once daily up to Week 144. |
Drug: TDF
300 mg tablets administered orally once daily
Other Names:
Drug: Placebo
Placebo administered orally once a week (every 7 days) for 12 doses
|
| Experimental: TDF + Vesatolimod 1 mg Main Study Phase:TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 1 mg tablet orally once a week (every 7 days) for 12 doses. Optional Treatment Extension Phase: At Week 48 participants had the option to continue TDF 300 mg tablets orally once daily up to Week 144. |
Drug: TDF
300 mg tablets administered orally once daily
Other Names:
Drug: Vesatolimod
Tablets administered orally once a week (every 7 days) for 12 doses
Other Names:
|
| Experimental: TDF + Vesatolimod 2 mg Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 2 mg tablet orally once a week (every 7 days) for 12 doses. Optional Treatment Extension Phase: At Week 48 participants had the option to continue TDF 300 mg tablets orally once daily up to Week 144. |
Drug: TDF
300 mg tablets administered orally once daily
Other Names:
Drug: Vesatolimod
Tablets administered orally once a week (every 7 days) for 12 doses
Other Names:
|
| Experimental: TDF + Vesatolimod 4 mg Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 4 mg tablet orally once a week (every 7 days) for 12 doses. Optional Treatment Extension Phase: At Week 48 participants had the option to continue TDF 300 mg tablets orally once daily up to Week 144. |
Drug: TDF
300 mg tablets administered orally once daily
Other Names:
Drug: Vesatolimod
Tablets administered orally once a week (every 7 days) for 12 doses
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Mean Change (Measured in log10 IU/mL) in Hepatitis B Surface Antigen (HBsAg) From Baseline at Week 24 [Baseline; Week 24]
The change from baseline to Week 24 in HBsAg (log10 IU/mL) was analyzed using a mixed model for repeated measures (MMRM). The model included treatment, baseline HBsAg (log10 IU/mL), baseline Hepatitis B Envelope Antigen (HBeAg) status (positive or negative), baseline alanine aminotransferase (ALT) level relative to upper limit of normal (ULN) (> 19 vs ≤ 19 IU/L for females; > 30 vs ≤ 30 IU/L for males), visit and treatment-by-visit interaction as fixed effects, and visit as a repeated measure.
Secondary Outcome Measures
- Percentage of Participants With HBeAg Loss and Seroconversion at Week 24 [Week 24]
HBeAg loss was defined as qualitative HBeAg result changing from positive at baseline to negative at any postbaseline visit. HBeAg seroconversion was defined as qualitative Hepatitis B Envelope Antibody (HBeAb) result changing from negative at baseline to positive at any postbaseline visit. The Missing (M) = Failure (F) approach was used for this analysis.
- Percentage of Participants With HBeAg Loss and Seroconversion at Week 48 [Week 48]
HBeAg loss was defined as qualitative HBeAg result changing from positive at baseline to negative at any postbaseline visit. HBeAg seroconversion was defined as qualitative HBeAb result changing from negative at baseline to positive at any postbaseline visit. The Missing (M) = Failure (F) approach was used for this analysis.
- Percentage of Participants With HBsAg Loss and Seroconversion at Week 24 [Week 24]
HBsAg loss was defined as qualitative HBsAg result changing from positive at baseline to negative at any postbaseline visit. HBsAg seroconversion was defined as qualitative Hepatitis B Surface Antibody (HBsAb) result changing from negative at baseline to positive at any postbaseline visit. The Missing (M) = Failure (F) approach was used for this analysis.
- Percentage of Participants With HBsAg Loss and Seroconversion at Week 48 [Week 48]
HBsAg loss was defined as qualitative HBsAg result changing from positive at baseline to negative at any postbaseline visit. HBsAg seroconversion was defined as qualitative HBsAb result changing from negative at baseline to positive at any postbaseline visit. The Missing (M) = Failure (F) approach was used for this analysis.
- Mean Change (Measured in log10 IU/mL) in HBsAg From Baseline at Week 12 [Baseline; Week 12]
- Mean Change (Measured in log10 IU/mL) in HBsAg From Baseline at Week 48 [Baseline; Week 48]
- Percentage of Participants With a ≥ 0.5 log10 IU/mL Decline in Serum HBsAg Titers From Baseline at Week 12 [Baseline to Week 12]
HBsAg ≥ 0.5 log10 IU/mL decline was defined as a decline from baseline in log10 IU/mL serum HBsAg ≥ 0.5 at the Week 12 post-baseline visit. Missing values were considered failures.
- Percentage of Participants With a ≥ 0.5 log10 IU/mL Decline in Serum HBsAg Titers From Baseline at Week 24 [Baseline to Week 24]
HBsAg ≥ 0.5 log10 IU/mL decline was defined as a decline from baseline in log10 IU/mL serum HBsAg ≥ 0.5 at the Week 24 post-baseline visit.
- Percentage of Participants With a ≥ 0.5 log10 IU/mL Decline in Serum HBsAg Titers From Baseline at Week 48 [Baseline to Week 48]
HBsAg ≥ 0.5 log10 IU/mL decline was defined as a decline from baseline in log10 IU/mL serum HBsAg ≥ 0.5 at the Week 12 post-baseline visit. Missing values were considered failures.
- Percentage of Participants With Hepatitis B Virus Deoxyribonucleic Acid (HBV DNA) < Lower Limit of Quantitation (LLOQ) at Week 24 [Week 24]
LLOQ for HBV DNA was defined as 20 IU/mL. The participants with missing information were excluded from the analysis.
- Percentage of Participants With HBV DNA < LLOQ at Week 48 [Week 48]
LLOQ for HBV DNA was defined as 20 IU/mL. The participants with missing information were excluded from the analysis.
- Percentage of Participants Experiencing Virologic Breakthrough [Weeks 24 and 48]
Virologic breakthrough was defined as confirmed HBV DNA ≥ 69 IU/mL after having had HBV DNA < 69 IU/mL or confirmed 1.0 log10 IU/mL or greater increase in HBV DNA from nadir. Confirmation requires 2 consecutive occurrences of elevation in HBV DNA to > 69 IU/mL after having had HBV DNA < 69 IU/mL or 1.0 log10 IU/mL or greater increases in HBV DNA from nadir.
- Number of Participants With Sequence Changes From Baseline Within the HBV Polymerase/Reverse Transcriptase (Pol/RT) [Baseline; Week 48]
Sequence analysis of the HBV pol/RT was attempted for any participant who had HBV DNA ≥ 69 IU/mL at Week 48 or early discontinuation. Results of the alignment of Week 48 and baseline sequence were reported as a change from baseline sequence.
- Pharmacokinetic (PK) Parameter: AUClast of Vesatolimod [Week 11: Predose, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose]
AUClast is defined as the area under the concentration versus time curve from time zero to the last quantifiable concentration.
- PK Parameter: AUCinf of Vesatolimod [Week 11: Predose, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose]
AUCinf is defined as the concentration of drug extrapolated to infinite time.
- PK Parameter: %AUCexp of Vesatolimod [Week 11: Predose, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose]
%AUCexp is defined as the percentage of AUC extrapolated between AUClast and AUCinf.
- PK Parameter: Cmax of Vesatolimod [Week 11: Predose, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose]
Cmax is defined as the maximum concentration of drug.
- PK Parameter: Clast of Vesatolimod [Week 11: Predose, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose]
Clast is defined as the last observable concentration of drug.
- PK Parameter: Tmax of Vesatolimod [Week 11: Predose, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose]
Tmax is defined as the time (observed time point) of Cmax
- PK Parameter: Tlast of Vesatolimod [Week 11: Predose, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose]
Tlast is defined as the time (observed time point) of Clast.
- PK Parameter: T1/2 of Vesatolimod [Week 11: Predose, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose]
T1/2 is defined as the estimate of the terminal elimination half-life of the drug.
- PK Parameter: CL/F of Vesatolimod [Week 11: Predose, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose]
CL/F is defined as the apparent oral clearance following administration of the drug.
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
to 65 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Key Inclusion Criteria:
-
Adult males or females between the ages of 18-65
-
Chronic hepatitis B virus (HBV) infection
-
HBV deoxyribonucleic acid (DNA ) ≥ 2000 IU/mL at screening
Key Exclusion Criteria:
-
Extensive bridging fibrosis or cirrhosis
-
Received oral antiviral treatment for HBV or prolonged therapy with immune-modulators or biologics within 3 months of screening
-
Co-infection with hepatitis C virus (HCV), human immunodeficiency virus (HIV) or hepatitis D virus (HDV)
-
Chronic liver disease other than HBV
-
Lactating or pregnant females or those that wish to become pregnant during the course of the study
Note: Other protocol defined Inclusion/Exclusion criteria may apply.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Los Angeles | California | United States | ||
| 2 | Palo Alto | California | United States | ||
| 3 | San Diego | California | United States | ||
| 4 | San Francisco | California | United States | ||
| 5 | Honolulu | Hawaii | United States | ||
| 6 | Catonsville | Maryland | United States | ||
| 7 | Boston | Massachusetts | United States | ||
| 8 | Flushing | New York | United States | ||
| 9 | Philadelphia | Pennsylvania | United States | ||
| 10 | Toronto | Ontario | Canada | ||
| 11 | Kowloon | Hong Kong | |||
| 12 | Bologna | Italy | |||
| 13 | Milano | Italy | |||
| 14 | Pisa | Italy | |||
| 15 | San Giovanni Rotondo | Italy | |||
| 16 | Daegu | Korea, Republic of | |||
| 17 | Seoul | Korea, Republic of | |||
| 18 | Grafton | Auckland | New Zealand | ||
| 19 | Dalin | Taiwan | |||
| 20 | Kaohsiung | Taiwan | |||
| 21 | London | United Kingdom |
Sponsors and Collaborators
- Gilead Sciences
Investigators
- Study Director: Gilead Study Director, Gilead Sciences
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.Responsible Party:
Gilead Sciences
ClinicalTrials.gov Identifier:
NCT02579382
Other Study ID Numbers:
- GS-US-283-1062
- 2015-002017-30
First Posted:
Oct 19, 2015
Last Update Posted:
May 18, 2020
Last Verified:
May 1, 2020
Individual Participant Data (IPD) Sharing Statement:
No
Plan to Share IPD:
No
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by Gilead Sciences
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | Participants were enrolled at study sites in Asia, Europe, New Zealand, and North America. The first participant was screened on 10 November 2015. The last study visit occurred on 03 May 2019. |
|---|---|
| Pre-assignment Detail | 260 participants were screened |
| Arm/Group Title | TDF + Placebo | TDF + Vesatolimod 1 mg | TDF + Vesatolimod 2 mg | TDF + Vesatolimod 4 mg |
|---|---|---|---|---|
| Arm/Group Description | Main Study Phase: Tenofovir disoproxil fumarate (TDF) 300 mg tablets orally once daily for up to 48 weeks + placebo administered orally once a week (every 7 days) for 12 doses. Optional Treatment Extension Phase: At Week 48 participants had the option to continue TDF 300 mg tablets orally once daily up to Week 144. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 1 mg tablet orally once a week (every 7 days) for 12 doses. Optional Treatment Extension Phase: At Week 48 participants had the option to continue TDF 300 mg tablets orally once daily up to Week 144. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 2 mg tablet orally once a week (every 7 days) for 12 doses. Optional Treatment Extension Phase: At Week 48 participants had the option to continue TDF 300 mg tablets orally once daily up to Week 144. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 4 mg tablet orally once a week (every 7 days) for 12 doses. Optional Treatment Extension Phase: At Week 48 participants had the option to continue TDF 300 mg tablets orally once daily up to Week 144. |
| Period Title: Main Study Phase | ||||
| STARTED | 28 | 53 | 56 | 55 |
| COMPLETED | 28 | 53 | 54 | 52 |
| NOT COMPLETED | 0 | 0 | 2 | 3 |
| Period Title: Main Study Phase | ||||
| STARTED | 27 | 51 | 54 | 49 |
| COMPLETED | 26 | 44 | 50 | 44 |
| NOT COMPLETED | 1 | 7 | 4 | 5 |
Baseline Characteristics
| Arm/Group Title | TDF + Placebo | TDF + Vesatolimod 1 mg | TDF + Vesatolimod 2 mg | TDF + Vesatolimod 4 mg | Total |
|---|---|---|---|---|---|
| Arm/Group Description | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + placebo administered orally once a week (every 7 days) for 12 doses. Optional Treatment Extension Phase: At Week 48 participants had the option to continue TDF 300 mg tablets orally once daily up to Week 144. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 1 mg tablet orally once a week (every 7 days) for 12 doses. Optional Treatment Extension Phase: At Week 48 participants had the option to continue TDF 300 mg tablets orally once daily up to Week 144. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 2 mg tablet orally once a week (every 7 days) for 12 doses. Optional Treatment Extension Phase: At Week 48 participants had the option to continue TDF 300 mg tablets orally once daily up to Week 144. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 4 mg tablet orally once a week (every 7 days) for 12 doses. Optional Treatment Extension Phase: At Week 48 participants had the option to continue TDF 300 mg tablets orally once daily up to Week 144. | Total of all reporting groups |
| Overall Participants | 28 | 53 | 56 | 55 | 192 |
| Age (years) [Mean (Standard Deviation) ] | |||||
| Mean (Standard Deviation) [years] |
41
(10.4)
|
41
(9.6)
|
44
(10.3)
|
44
(10.3)
|
42
(10.1)
|
| Sex: Female, Male (Count of Participants) | |||||
| Female |
12
42.9%
|
21
39.6%
|
16
28.6%
|
20
36.4%
|
69
35.9%
|
| Male |
16
57.1%
|
32
60.4%
|
40
71.4%
|
35
63.6%
|
123
64.1%
|
| Race/Ethnicity, Customized (Count of Participants) | |||||
| Asian |
22
78.6%
|
41
77.4%
|
48
85.7%
|
44
80%
|
155
80.7%
|
| White |
4
14.3%
|
6
11.3%
|
5
8.9%
|
10
18.2%
|
25
13%
|
| Black or African American |
1
3.6%
|
5
9.4%
|
3
5.4%
|
0
0%
|
9
4.7%
|
| Native Hawaiian or Pacific Islander |
1
3.6%
|
0
0%
|
0
0%
|
1
1.8%
|
2
1%
|
| Other |
0
0%
|
1
1.9%
|
0
0%
|
0
0%
|
1
0.5%
|
| Race/Ethnicity, Customized (Count of Participants) | |||||
| Hispanic or Latino |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Not Hispanic or Latino |
28
100%
|
53
100%
|
56
100%
|
55
100%
|
192
100%
|
| Not Permitted |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Region of Enrollment (participants) [Number] | |||||
| New Zealand |
1
3.6%
|
0
0%
|
1
1.8%
|
3
5.5%
|
5
2.6%
|
| Canada |
2
7.1%
|
8
15.1%
|
9
16.1%
|
4
7.3%
|
23
12%
|
| South Korea |
7
25%
|
12
22.6%
|
17
30.4%
|
15
27.3%
|
51
26.6%
|
| Hong Kong |
0
0%
|
3
5.7%
|
0
0%
|
2
3.6%
|
5
2.6%
|
| United States |
6
21.4%
|
14
26.4%
|
13
23.2%
|
10
18.2%
|
43
22.4%
|
| Taiwan |
5
17.9%
|
4
7.5%
|
6
10.7%
|
6
10.9%
|
21
10.9%
|
| Italy |
6
21.4%
|
8
15.1%
|
6
10.7%
|
12
21.8%
|
32
16.7%
|
| United Kingdom |
1
3.6%
|
4
7.5%
|
4
7.1%
|
3
5.5%
|
12
6.3%
|
| Serum Hepatitis B Surface Antigen (HBsAg) (log10 IU/mL) (log10 IU/mL) [Mean (Standard Deviation) ] | |||||
| Mean (Standard Deviation) [log10 IU/mL] |
3.8
(0.84)
|
3.7
(0.84)
|
3.5
(0.88)
|
3.6
(0.74)
|
3.6
(0.82)
|
| Hepatitis B Envelope Antigen (HBeAg) Status (Count of Participants) | |||||
| HBeAg Status- Negative |
17
60.7%
|
33
62.3%
|
33
58.9%
|
34
61.8%
|
117
60.9%
|
| HBeAg Status- Positive |
11
39.3%
|
20
37.7%
|
23
41.1%
|
21
38.2%
|
75
39.1%
|
| Hepatitis B Virus (HBV) DNA (log10 IU/mL) [Mean (Standard Deviation) ] | |||||
| Mean (Standard Deviation) [log10 IU/mL] |
5.9
(2.10)
|
5.9
(1.80)
|
5.6
(1.85)
|
5.9
(1.70)
|
5.8
(1.82)
|
Outcome Measures
| Title | Mean Change (Measured in log10 IU/mL) in Hepatitis B Surface Antigen (HBsAg) From Baseline at Week 24 |
|---|---|
| Description | The change from baseline to Week 24 in HBsAg (log10 IU/mL) was analyzed using a mixed model for repeated measures (MMRM). The model included treatment, baseline HBsAg (log10 IU/mL), baseline Hepatitis B Envelope Antigen (HBeAg) status (positive or negative), baseline alanine aminotransferase (ALT) level relative to upper limit of normal (ULN) (> 19 vs ≤ 19 IU/L for females; > 30 vs ≤ 30 IU/L for males), visit and treatment-by-visit interaction as fixed effects, and visit as a repeated measure. |
| Time Frame | Baseline; Week 24 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The Full Analysis Set included all participants who were randomized and took at least 1 dose of study drug. |
| Arm/Group Title | TDF + Placebo | TDF + Vesatolimod 1 mg | TDF + Vesatolimod 2 mg | TDF + Vesatolimod 4 mg |
|---|---|---|---|---|
| Arm/Group Description | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + Placebo administered orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 1 mg tablet orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 2 mg tablet orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 4 mg tablet orally once a week (every 7 days) for 12 doses. |
| Measure Participants | 28 | 53 | 54 | 54 |
| Least Squares Mean (95% Confidence Interval) [log10 IU/mL] |
-0.163
|
-0.056
|
-0.146
|
-0.036
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | TDF + Placebo, TDF + Vesatolimod 1 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.227 |
| Comments | MMRM model included treatment, baseline ALT level, HBeAg baseline status, baseline HBsAg, visit and treatment-by-visit interaction as fixed effect and visit as repeated measurement. | |
| Method | MMRM | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Least Squares Mean Difference |
| Estimated Value | 0.107 | |
| Confidence Interval |
(2-Sided) 95% -0.067 to 0.282 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | TDF + Placebo, TDF + Vesatolimod 2 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.840 |
| Comments | MMRM model included treatment, baseline ALT level, HBeAg baseline status, baseline HBsAg, visit and treatment-by-visit interaction as fixed effect and visit as repeated measurement. | |
| Method | MMRM | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Least Squares Mean Difference |
| Estimated Value | 0.018 | |
| Confidence Interval |
(2-Sided) 95% -0.156 to 0.191 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | TDF + Placebo, TDF + Vesatolimod 4 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.151 |
| Comments | MMRM model included treatment, baseline ALT level, HBeAg baseline status, baseline HBsAg, visit and treatment-by-visit interaction as fixed effect and visit as repeated measurement. | |
| Method | MMRM | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Least Squares Mean Difference |
| Estimated Value | 0.127 | |
| Confidence Interval |
(2-Sided) 95% -0.047 to 0.301 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Percentage of Participants With HBeAg Loss and Seroconversion at Week 24 |
|---|---|
| Description | HBeAg loss was defined as qualitative HBeAg result changing from positive at baseline to negative at any postbaseline visit. HBeAg seroconversion was defined as qualitative Hepatitis B Envelope Antibody (HBeAb) result changing from negative at baseline to positive at any postbaseline visit. The Missing (M) = Failure (F) approach was used for this analysis. |
| Time Frame | Week 24 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants in the Full Analysis Set who were HBeAg positive at baseline were analyzed. |
| Arm/Group Title | TDF + Placebo | TDF + Vesatolimod 1 mg | TDF + Vesatolimod 2 mg | TDF + Vesatolimod 4 mg |
|---|---|---|---|---|
| Arm/Group Description | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + placebo administered orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 1 mg tablet orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 2 mg tablet orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 4 mg tablet orally once a week (every 7 days) for 12 doses. |
| Measure Participants | 11 | 20 | 23 | 21 |
| Number [percentage of participants] |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Title | Percentage of Participants With HBeAg Loss and Seroconversion at Week 48 |
|---|---|
| Description | HBeAg loss was defined as qualitative HBeAg result changing from positive at baseline to negative at any postbaseline visit. HBeAg seroconversion was defined as qualitative HBeAb result changing from negative at baseline to positive at any postbaseline visit. The Missing (M) = Failure (F) approach was used for this analysis. |
| Time Frame | Week 48 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants in the Full Analysis Set who were HBeAg positive at baseline were analyzed. |
| Arm/Group Title | TDF + Placebo | TDF + Vesatolimod 1 mg | TDF + Vesatolimod 2 mg | TDF + Vesatolimod 4 mg |
|---|---|---|---|---|
| Arm/Group Description | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + placebo administered orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 1 mg tablet orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 2 mg tablet orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 4 mg tablet orally once a week (every 7 days) for 12 doses. |
| Measure Participants | 11 | 20 | 23 | 21 |
| Number [percentage of participants] |
0
0%
|
5.0
9.4%
|
4.3
7.7%
|
4.8
8.7%
|
| Title | Percentage of Participants With HBsAg Loss and Seroconversion at Week 24 |
|---|---|
| Description | HBsAg loss was defined as qualitative HBsAg result changing from positive at baseline to negative at any postbaseline visit. HBsAg seroconversion was defined as qualitative Hepatitis B Surface Antibody (HBsAb) result changing from negative at baseline to positive at any postbaseline visit. The Missing (M) = Failure (F) approach was used for this analysis. |
| Time Frame | Week 24 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants in the Full Analysis Set who were HBsAg positive at baseline were analyzed. |
| Arm/Group Title | TDF + Placebo | TDF + Vesatolimod 1 mg | TDF + Vesatolimod 2 mg | TDF + Vesatolimod 4 mg |
|---|---|---|---|---|
| Arm/Group Description | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + placebo administered orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 1 mg tablet orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 2 mg tablet orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 4 mg tablet orally once a week (every 7 days) for 12 doses. |
| Measure Participants | 28 | 53 | 56 | 55 |
| Number [percentage of participants] |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Title | Percentage of Participants With HBsAg Loss and Seroconversion at Week 48 |
|---|---|
| Description | HBsAg loss was defined as qualitative HBsAg result changing from positive at baseline to negative at any postbaseline visit. HBsAg seroconversion was defined as qualitative HBsAb result changing from negative at baseline to positive at any postbaseline visit. The Missing (M) = Failure (F) approach was used for this analysis. |
| Time Frame | Week 48 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants in the Full Analysis Set who were HBsAg positive at baseline were analyzed. |
| Arm/Group Title | TDF + Placebo | TDF + Vesatolimod 1 mg | TDF + Vesatolimod 2 mg | TDF + Vesatolimod 4 mg |
|---|---|---|---|---|
| Arm/Group Description | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + placebo administered orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 1 mg tablet orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 2 mg tablet orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 4 mg tablet orally once a week (every 7 days) for 12 doses. |
| Measure Participants | 28 | 53 | 56 | 55 |
| Number [percentage of participants] |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Title | Mean Change (Measured in log10 IU/mL) in HBsAg From Baseline at Week 12 |
|---|---|
| Description | |
| Time Frame | Baseline; Week 12 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants in the Full Analysis Set with available data were analyzed. |
| Arm/Group Title | TDF + Placebo | TDF + Vesatolimod 1 mg | TDF + Vesatolimod 2 mg | TDF + Vesatolimod 4 mg |
|---|---|---|---|---|
| Arm/Group Description | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + placebo administered orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 1 mg tablet orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 2 mg tablet orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 4 mg tablet orally once a week (every 7 days) for 12 doses. |
| Measure Participants | 27 | 53 | 55 | 52 |
| Mean (Standard Deviation) [log10 IU/mL] |
-0.087
(0.2199)
|
-0.041
(0.2283)
|
-0.138
(0.5247)
|
-0.020
(0.2668)
|
| Title | Mean Change (Measured in log10 IU/mL) in HBsAg From Baseline at Week 48 |
|---|---|
| Description | |
| Time Frame | Baseline; Week 48 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants in the Full Analysis Set with available data were analyzed. |
| Arm/Group Title | TDF + Placebo | TDF + Vesatolimod 1 mg | TDF + Vesatolimod 2 mg | TDF + Vesatolimod 4 mg |
|---|---|---|---|---|
| Arm/Group Description | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + placebo administered orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 1 mg tablet orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 2 mg tablet orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 4 mg tablet orally once a week (every 7 days) for 12 doses. |
| Measure Participants | 28 | 53 | 54 | 53 |
| Mean (Standard Deviation) [log10 IU/mL] |
-0.338
(0.8922)
|
-0.079
(0.2912)
|
-0.197
(0.5757)
|
-0.088
(0.3700)
|
| Title | Percentage of Participants With a ≥ 0.5 log10 IU/mL Decline in Serum HBsAg Titers From Baseline at Week 12 |
|---|---|
| Description | HBsAg ≥ 0.5 log10 IU/mL decline was defined as a decline from baseline in log10 IU/mL serum HBsAg ≥ 0.5 at the Week 12 post-baseline visit. Missing values were considered failures. |
| Time Frame | Baseline to Week 12 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants in the Full Analysis Set were analyzed. |
| Arm/Group Title | TDF + Placebo | TDF + Vesatolimod 1 mg | TDF + Vesatolimod 2 mg | TDF + Vesatolimod 4 mg |
|---|---|---|---|---|
| Arm/Group Description | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + placebo administered orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 1 mg tablet orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 2 mg tablet orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 4 mg tablet orally once a week (every 7 days) for 12 doses. |
| Measure Participants | 28 | 53 | 56 | 55 |
| Number [percentage of participants] |
7.1
25.4%
|
3.8
7.2%
|
10.7
19.1%
|
1.8
3.3%
|
| Title | Percentage of Participants With a ≥ 0.5 log10 IU/mL Decline in Serum HBsAg Titers From Baseline at Week 24 |
|---|---|
| Description | HBsAg ≥ 0.5 log10 IU/mL decline was defined as a decline from baseline in log10 IU/mL serum HBsAg ≥ 0.5 at the Week 24 post-baseline visit. |
| Time Frame | Baseline to Week 24 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants in the Full Analysis Set were analyzed. |
| Arm/Group Title | TDF + Placebo | TDF + Vesatolimod 1 mg | TDF + Vesatolimod 2 mg | TDF + Vesatolimod 4 mg |
|---|---|---|---|---|
| Arm/Group Description | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + placebo administered orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 1 mg tablet orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 2 mg tablet orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 4 mg tablet orally once a week (every 7 days) for 12 doses. |
| Measure Participants | 28 | 53 | 56 | 55 |
| Number [percentage of participants] |
10.7
38.2%
|
3.8
7.2%
|
10.7
19.1%
|
3.6
6.5%
|
| Title | Percentage of Participants With a ≥ 0.5 log10 IU/mL Decline in Serum HBsAg Titers From Baseline at Week 48 |
|---|---|
| Description | HBsAg ≥ 0.5 log10 IU/mL decline was defined as a decline from baseline in log10 IU/mL serum HBsAg ≥ 0.5 at the Week 12 post-baseline visit. Missing values were considered failures. |
| Time Frame | Baseline to Week 48 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants in the Full Analysis Set were analyzed. |
| Arm/Group Title | TDF + Placebo | TDF + Vesatolimod 1 mg | TDF + Vesatolimod 2 mg | TDF + Vesatolimod 4 mg |
|---|---|---|---|---|
| Arm/Group Description | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + placebo administered orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 1 mg tablet orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 2 mg tablet orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 4 mg tablet orally once a week (every 7 days) for 12 doses. |
| Measure Participants | 28 | 53 | 56 | 55 |
| Number [percentage of participants] |
17.9
63.9%
|
5.7
10.8%
|
16.1
28.8%
|
14.5
26.4%
|
| Title | Percentage of Participants With Hepatitis B Virus Deoxyribonucleic Acid (HBV DNA) < Lower Limit of Quantitation (LLOQ) at Week 24 |
|---|---|
| Description | LLOQ for HBV DNA was defined as 20 IU/mL. The participants with missing information were excluded from the analysis. |
| Time Frame | Week 24 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants in the Full Analysis Set were analyzed. |
| Arm/Group Title | TDF + Placebo | TDF + Vesatolimod 1 mg | TDF + Vesatolimod 2 mg | TDF + Vesatolimod 4 mg |
|---|---|---|---|---|
| Arm/Group Description | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + placebo administered orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 1 mg tablet orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 2 mg tablet orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 4 mg tablet orally once a week (every 7 days) for 12 doses. |
| Measure Participants | 28 | 53 | 56 | 55 |
| Number [percentage of participants] |
53.6
191.4%
|
58.5
110.4%
|
59.3
105.9%
|
63.0
114.5%
|
| Title | Percentage of Participants With HBV DNA < LLOQ at Week 48 |
|---|---|
| Description | LLOQ for HBV DNA was defined as 20 IU/mL. The participants with missing information were excluded from the analysis. |
| Time Frame | Week 48 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants in the Full Analysis Set were analyzed. |
| Arm/Group Title | TDF + Placebo | TDF + Vesatolimod 1 mg | TDF + Vesatolimod 2 mg | TDF + Vesatolimod 4 mg |
|---|---|---|---|---|
| Arm/Group Description | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + placebo administered orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 1 mg tablet orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 2 mg tablet orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 4 mg tablet orally once a week (every 7 days) for 12 doses. |
| Measure Participants | 28 | 53 | 56 | 55 |
| Number [percentage of participants] |
64.3
229.6%
|
62.3
117.5%
|
75.9
135.5%
|
75.5
137.3%
|
| Title | Percentage of Participants Experiencing Virologic Breakthrough |
|---|---|
| Description | Virologic breakthrough was defined as confirmed HBV DNA ≥ 69 IU/mL after having had HBV DNA < 69 IU/mL or confirmed 1.0 log10 IU/mL or greater increase in HBV DNA from nadir. Confirmation requires 2 consecutive occurrences of elevation in HBV DNA to > 69 IU/mL after having had HBV DNA < 69 IU/mL or 1.0 log10 IU/mL or greater increases in HBV DNA from nadir. |
| Time Frame | Weeks 24 and 48 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants in the Full Analysis Set were analyzed. |
| Arm/Group Title | TDF + Placebo | TDF + Vesatolimod 1 mg | TDF + Vesatolimod 2 mg | TDF + Vesatolimod 4 mg |
|---|---|---|---|---|
| Arm/Group Description | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + placebo administered orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 1 mg tablet orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 2 mg tablet orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 4 mg tablet orally once a week (every 7 days) for 12 doses. |
| Measure Participants | 28 | 53 | 56 | 55 |
| Week 24 |
0
0%
|
0
0%
|
1.8
3.2%
|
0
0%
|
| Week 48 |
0
0%
|
3.8
7.2%
|
1.8
3.2%
|
0
0%
|
| Title | Number of Participants With Sequence Changes From Baseline Within the HBV Polymerase/Reverse Transcriptase (Pol/RT) |
|---|---|
| Description | Sequence analysis of the HBV pol/RT was attempted for any participant who had HBV DNA ≥ 69 IU/mL at Week 48 or early discontinuation. Results of the alignment of Week 48 and baseline sequence were reported as a change from baseline sequence. |
| Time Frame | Baseline; Week 48 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants in the Full Analysis Set with available data were analyzed. |
| Arm/Group Title | TDF + Placebo | TDF + Vesatolimod 1 mg | TDF + Vesatolimod 2 mg | TDF + Vesatolimod 4 mg |
|---|---|---|---|---|
| Arm/Group Description | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + placebo administered orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 1 mg tablet orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 2 mg tablet orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 4 mg tablet orally once a week (every 7 days) for 12 doses. |
| Measure Participants | 5 | 13 | 5 | 7 |
| Count of Participants [Participants] |
2
7.1%
|
4
7.5%
|
2
3.6%
|
2
3.6%
|
| Title | Pharmacokinetic (PK) Parameter: AUClast of Vesatolimod |
|---|---|
| Description | AUClast is defined as the area under the concentration versus time curve from time zero to the last quantifiable concentration. |
| Time Frame | Week 11: Predose, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose |
Outcome Measure Data
| Analysis Population Description |
|---|
| The PK Substudy Analysis Set included all randomized participants who took at least 1 dose of vesatolimod, participated in the PK substudy, and had at least 1 non-missing steady state PK parameter. |
| Arm/Group Title | TDF + Vesatolimod 1 mg | TDF + Vesatolimod 2 mg | TDF + Vesatolimod 4 mg |
|---|---|---|---|
| Arm/Group Description | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 1 mg tablet orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 2 mg tablet orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 4 mg tablet orally once a week (every 7 days) for 12 doses. |
| Measure Participants | 5 | 5 | 4 |
| Mean (Standard Deviation) [hour*picogram/milliliter (h*pg/mL)] |
5252.3
(5756.26)
|
7170.6
(4569.83)
|
28537.2
(23608.94)
|
| Title | PK Parameter: AUCinf of Vesatolimod |
|---|---|
| Description | AUCinf is defined as the concentration of drug extrapolated to infinite time. |
| Time Frame | Week 11: Predose, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants in the PK Substudy Analysis Set with available data were analyzed. |
| Arm/Group Title | TDF + Vesatolimod 1 mg | TDF + Vesatolimod 2 mg | TDF + Vesatolimod 4 mg |
|---|---|---|---|
| Arm/Group Description | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 1 mg tablet orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 2 mg tablet orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 4 mg tablet orally once a week (every 7 days) for 12 doses. |
| Measure Participants | 5 | 5 | 4 |
| Mean (Standard Deviation) [h*pg/mL] |
7277.3
(6550.71)
|
10239.0
(6243.75)
|
34534.8
(26482.89)
|
| Title | PK Parameter: %AUCexp of Vesatolimod |
|---|---|
| Description | %AUCexp is defined as the percentage of AUC extrapolated between AUClast and AUCinf. |
| Time Frame | Week 11: Predose, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants in the PK Substudy Analysis Set were analyzed. |
| Arm/Group Title | TDF + Vesatolimod 1 mg | TDF + Vesatolimod 2 mg | TDF + Vesatolimod 4 mg |
|---|---|---|---|
| Arm/Group Description | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 1 mg tablet orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 2 mg tablet orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 4 mg tablet orally once a week (every 7 days) for 12 doses. |
| Measure Participants | 5 | 5 | 4 |
| Mean (Standard Deviation) [Percentage of AUC] |
31.1
(19.70)
|
28.6
(11.42)
|
19.3
(6.15)
|
| Title | PK Parameter: Cmax of Vesatolimod |
|---|---|
| Description | Cmax is defined as the maximum concentration of drug. |
| Time Frame | Week 11: Predose, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants in the PK Substudy Analysis Set were analyzed. |
| Arm/Group Title | TDF + Vesatolimod 1 mg | TDF + Vesatolimod 2 mg | TDF + Vesatolimod 4 mg |
|---|---|---|---|
| Arm/Group Description | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 1 mg tablet orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 2 mg tablet orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 4 mg tablet orally once a week (every 7 days) for 12 doses. |
| Measure Participants | 5 | 5 | 4 |
| Mean (Standard Deviation) [picogram/milliliter (pg/mL)] |
667.8
(785.44)
|
850.4
(569.75)
|
4957.5
(5035.46)
|
| Title | PK Parameter: Clast of Vesatolimod |
|---|---|
| Description | Clast is defined as the last observable concentration of drug. |
| Time Frame | Week 11: Predose, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants in the PK Substudy Analysis Set were analyzed. |
| Arm/Group Title | TDF + Vesatolimod 1 mg | TDF + Vesatolimod 2 mg | TDF + Vesatolimod 4 mg |
|---|---|---|---|
| Arm/Group Description | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 1 mg tablet orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 2 mg tablet orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 4 mg tablet orally once a week (every 7 days) for 12 doses. |
| Measure Participants | 5 | 5 | 4 |
| Mean (Standard Deviation) [pg/mL] |
92.8
(73.80)
|
119.0
(74.45)
|
328.0
(165.19)
|
| Title | PK Parameter: Tmax of Vesatolimod |
|---|---|
| Description | Tmax is defined as the time (observed time point) of Cmax |
| Time Frame | Week 11: Predose, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants in the PK Substudy Analysis Set were analyzed. |
| Arm/Group Title | TDF + Vesatolimod 1 mg | TDF + Vesatolimod 2 mg | TDF + Vesatolimod 4 mg |
|---|---|---|---|
| Arm/Group Description | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 1 mg tablet orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 2 mg tablet orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 4 mg tablet orally once a week (every 7 days) for 12 doses. |
| Measure Participants | 5 | 5 | 4 |
| Median (Full Range) [hours] |
1.00
|
2.00
|
3.00
|
| Title | PK Parameter: Tlast of Vesatolimod |
|---|---|
| Description | Tlast is defined as the time (observed time point) of Clast. |
| Time Frame | Week 11: Predose, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants in the PK Substudy Analysis Set were analyzed. |
| Arm/Group Title | TDF + Vesatolimod 1 mg | TDF + Vesatolimod 2 mg | TDF + Vesatolimod 4 mg |
|---|---|---|---|
| Arm/Group Description | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 1 mg tablet orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 2 mg tablet orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 4 mg tablet orally once a week (every 7 days) for 12 doses. |
| Measure Participants | 5 | 5 | 4 |
| Median (Full Range) [hours] |
24.00
|
24.00
|
24.00
|
| Title | PK Parameter: T1/2 of Vesatolimod |
|---|---|
| Description | T1/2 is defined as the estimate of the terminal elimination half-life of the drug. |
| Time Frame | Week 11: Predose, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants in the PK Substudy Analysis Set were analyzed. |
| Arm/Group Title | TDF + Vesatolimod 1 mg | TDF + Vesatolimod 2 mg | TDF + Vesatolimod 4 mg |
|---|---|---|---|
| Arm/Group Description | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 1 mg tablet orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 2 mg tablet orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 4 mg tablet orally once a week (every 7 days) for 12 doses. |
| Measure Participants | 5 | 5 | 4 |
| Median (Full Range) [hours] |
10.79
|
14.12
|
13.32
|
| Title | PK Parameter: CL/F of Vesatolimod |
|---|---|
| Description | CL/F is defined as the apparent oral clearance following administration of the drug. |
| Time Frame | Week 11: Predose, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants in the PK Substudy Analysis Set were analyzed. |
| Arm/Group Title | TDF + Vesatolimod 1 mg | TDF + Vesatolimod 2 mg | TDF + Vesatolimod 4 mg |
|---|---|---|---|
| Arm/Group Description | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 1 mg tablet orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 2 mg tablet orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 4 mg tablet orally once a week (every 7 days) for 12 doses. |
| Measure Participants | 5 | 5 | 4 |
| Mean (Standard Deviation) [liter/hour] |
273.9
(270.58)
|
262.3
(144.45)
|
156.2
(72.48)
|
Adverse Events
| Time Frame | First dose date up to last dose of study drug (Maximum: 144 weeks) | |||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | The Safety Analysis Set included all participants who took at least 1 dose of study drug. | |||||||||||||||
| Arm/Group Title | TDF + Placebo | TDF + Vesatolimod 1 mg | TDF + Vesatolimod 2 mg | TDF + Vesatolimod 4 mg | TDF Extension From TDF + Placebo | TDF Extension From TDF + Vesatolimod 1 mg | TDF Extension From TDF + Vesatolimod 2 mg | TDF Extension From TDF + Vesatolimod 4 mg | ||||||||
| Arm/Group Description | Main Study Phase: Tenofovir disoproxil fumarate (TDF) 300 mg tablets orally once daily for up to 48 weeks + placebo administered orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod (GS 9620) 1 mg tablet orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 2 mg tablet orally once a week (every 7 days) for 12 doses. | Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 4 mg tablet orally once a week (every 7 days) for 12 doses. | Optional Treatment Extension Phase: At Week 48 participants had the option to continue TDF 300 mg tablets orally once daily up to Week 144; Includes participants who received TDF + Placebo in the Main Study Phase. | Optional Treatment Extension Phase: At Week 48 participants had the option to continue TDF 300 mg tablets orally once daily up to Week 144; includes participants who received TDF + Vesatolimod 1 mg in the Main Study Phase. | Optional Treatment Extension Phase: At Week 48 participants had the option to continue TDF 300 mg tablets orally once daily up to Week 144; includes participants who received TDF + Vesatolimod 2 mg in the Main Study Phase. | Optional Treatment Extension Phase: At Week 48 participants had the option to continue TDF 300 mg tablets orally once daily up to Week 144; includes participants who received TDF + Vesatolimod 4 mg in the Main Study Phase. | ||||||||
All Cause Mortality |
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| TDF + Placebo | TDF + Vesatolimod 1 mg | TDF + Vesatolimod 2 mg | TDF + Vesatolimod 4 mg | TDF Extension From TDF + Placebo | TDF Extension From TDF + Vesatolimod 1 mg | TDF Extension From TDF + Vesatolimod 2 mg | TDF Extension From TDF + Vesatolimod 4 mg | |||||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/28 (0%) | 0/53 (0%) | 0/56 (0%) | 0/55 (0%) | 0/27 (0%) | 0/51 (0%) | 0/54 (0%) | 0/49 (0%) | ||||||||
Serious Adverse Events |
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| TDF + Placebo | TDF + Vesatolimod 1 mg | TDF + Vesatolimod 2 mg | TDF + Vesatolimod 4 mg | TDF Extension From TDF + Placebo | TDF Extension From TDF + Vesatolimod 1 mg | TDF Extension From TDF + Vesatolimod 2 mg | TDF Extension From TDF + Vesatolimod 4 mg | |||||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/28 (0%) | 1/53 (1.9%) | 1/56 (1.8%) | 1/55 (1.8%) | 1/27 (3.7%) | 4/51 (7.8%) | 5/54 (9.3%) | 1/49 (2%) | ||||||||
| Gastrointestinal disorders | ||||||||||||||||
| Abdominal pain | 0/28 (0%) | 0/53 (0%) | 0/56 (0%) | 1/55 (1.8%) | 0/27 (0%) | 0/51 (0%) | 0/54 (0%) | 0/49 (0%) | ||||||||
| Large intestine polyp | 0/28 (0%) | 0/53 (0%) | 0/56 (0%) | 0/55 (0%) | 0/27 (0%) | 0/51 (0%) | 1/54 (1.9%) | 0/49 (0%) | ||||||||
| General disorders | ||||||||||||||||
| Chest pain | 0/28 (0%) | 0/53 (0%) | 0/56 (0%) | 0/55 (0%) | 0/27 (0%) | 0/51 (0%) | 1/54 (1.9%) | 0/49 (0%) | ||||||||
| Pyrexia | 0/28 (0%) | 0/53 (0%) | 0/56 (0%) | 0/55 (0%) | 0/27 (0%) | 0/51 (0%) | 0/54 (0%) | 1/49 (2%) | ||||||||
| Injury, poisoning and procedural complications | ||||||||||||||||
| Skin laceration | 0/28 (0%) | 1/53 (1.9%) | 0/56 (0%) | 0/55 (0%) | 0/27 (0%) | 0/51 (0%) | 0/54 (0%) | 0/49 (0%) | ||||||||
| Tendon rupture | 0/28 (0%) | 0/53 (0%) | 0/56 (0%) | 0/55 (0%) | 0/27 (0%) | 0/51 (0%) | 1/54 (1.9%) | 0/49 (0%) | ||||||||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||||||||||||
| Breast cancer | 0/28 (0%) | 0/53 (0%) | 0/56 (0%) | 0/55 (0%) | 0/27 (0%) | 1/51 (2%) | 0/54 (0%) | 0/49 (0%) | ||||||||
| Hepatocellular carcinoma | 0/28 (0%) | 0/53 (0%) | 0/56 (0%) | 0/55 (0%) | 0/27 (0%) | 2/51 (3.9%) | 1/54 (1.9%) | 0/49 (0%) | ||||||||
| Leiomyoma | 0/28 (0%) | 0/53 (0%) | 0/56 (0%) | 0/55 (0%) | 1/27 (3.7%) | 0/51 (0%) | 0/54 (0%) | 0/49 (0%) | ||||||||
| Nervous system disorders | ||||||||||||||||
| Facial paralysis | 0/28 (0%) | 0/53 (0%) | 0/56 (0%) | 0/55 (0%) | 0/27 (0%) | 0/51 (0%) | 1/54 (1.9%) | 0/49 (0%) | ||||||||
| Hemiparesis | 0/28 (0%) | 0/53 (0%) | 0/56 (0%) | 0/55 (0%) | 0/27 (0%) | 0/51 (0%) | 1/54 (1.9%) | 0/49 (0%) | ||||||||
| Transient ischaemic attack | 0/28 (0%) | 0/53 (0%) | 0/56 (0%) | 0/55 (0%) | 0/27 (0%) | 0/51 (0%) | 1/54 (1.9%) | 0/49 (0%) | ||||||||
| Reproductive system and breast disorders | ||||||||||||||||
| Adenomyosis | 0/28 (0%) | 0/53 (0%) | 0/56 (0%) | 0/55 (0%) | 0/27 (0%) | 1/51 (2%) | 0/54 (0%) | 0/49 (0%) | ||||||||
| Pelvic congestion | 0/28 (0%) | 0/53 (0%) | 0/56 (0%) | 0/55 (0%) | 0/27 (0%) | 0/51 (0%) | 1/54 (1.9%) | 0/49 (0%) | ||||||||
| Uterine haemorrhage | 0/28 (0%) | 0/53 (0%) | 0/56 (0%) | 0/55 (0%) | 1/27 (3.7%) | 0/51 (0%) | 0/54 (0%) | 0/49 (0%) | ||||||||
| Uterine polyp | 0/28 (0%) | 0/53 (0%) | 0/56 (0%) | 0/55 (0%) | 0/27 (0%) | 0/51 (0%) | 1/54 (1.9%) | 0/49 (0%) | ||||||||
| Respiratory, thoracic and mediastinal disorders | ||||||||||||||||
| Asthma | 0/28 (0%) | 0/53 (0%) | 1/56 (1.8%) | 0/55 (0%) | 0/27 (0%) | 0/51 (0%) | 0/54 (0%) | 0/49 (0%) | ||||||||
Other (Not Including Serious) Adverse Events |
||||||||||||||||
| TDF + Placebo | TDF + Vesatolimod 1 mg | TDF + Vesatolimod 2 mg | TDF + Vesatolimod 4 mg | TDF Extension From TDF + Placebo | TDF Extension From TDF + Vesatolimod 1 mg | TDF Extension From TDF + Vesatolimod 2 mg | TDF Extension From TDF + Vesatolimod 4 mg | |||||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 14/28 (50%) | 25/53 (47.2%) | 27/56 (48.2%) | 33/55 (60%) | 7/27 (25.9%) | 14/51 (27.5%) | 13/54 (24.1%) | 12/49 (24.5%) | ||||||||
| Gastrointestinal disorders | ||||||||||||||||
| Abdominal distension | 2/28 (7.1%) | 3/53 (5.7%) | 1/56 (1.8%) | 1/55 (1.8%) | 0/27 (0%) | 0/51 (0%) | 0/54 (0%) | 2/49 (4.1%) | ||||||||
| Abdominal pain upper | 2/28 (7.1%) | 3/53 (5.7%) | 1/56 (1.8%) | 0/55 (0%) | 0/27 (0%) | 2/51 (3.9%) | 1/54 (1.9%) | 1/49 (2%) | ||||||||
| Diarrhoea | 0/28 (0%) | 4/53 (7.5%) | 2/56 (3.6%) | 5/55 (9.1%) | 0/27 (0%) | 1/51 (2%) | 1/54 (1.9%) | 1/49 (2%) | ||||||||
| Dyspepsia | 2/28 (7.1%) | 1/53 (1.9%) | 3/56 (5.4%) | 1/55 (1.8%) | 1/27 (3.7%) | 0/51 (0%) | 1/54 (1.9%) | 1/49 (2%) | ||||||||
| Nausea | 3/28 (10.7%) | 5/53 (9.4%) | 3/56 (5.4%) | 5/55 (9.1%) | 0/27 (0%) | 0/51 (0%) | 2/54 (3.7%) | 0/49 (0%) | ||||||||
| Vomiting | 0/28 (0%) | 2/53 (3.8%) | 0/56 (0%) | 5/55 (9.1%) | 0/27 (0%) | 0/51 (0%) | 0/54 (0%) | 0/49 (0%) | ||||||||
| General disorders | ||||||||||||||||
| Asthenia | 2/28 (7.1%) | 1/53 (1.9%) | 2/56 (3.6%) | 3/55 (5.5%) | 0/27 (0%) | 1/51 (2%) | 0/54 (0%) | 0/49 (0%) | ||||||||
| Chills | 1/28 (3.6%) | 2/53 (3.8%) | 6/56 (10.7%) | 10/55 (18.2%) | 0/27 (0%) | 0/51 (0%) | 1/54 (1.9%) | 0/49 (0%) | ||||||||
| Fatigue | 6/28 (21.4%) | 8/53 (15.1%) | 6/56 (10.7%) | 14/55 (25.5%) | 0/27 (0%) | 2/51 (3.9%) | 1/54 (1.9%) | 2/49 (4.1%) | ||||||||
| Influenza like illness | 1/28 (3.6%) | 1/53 (1.9%) | 0/56 (0%) | 5/55 (9.1%) | 0/27 (0%) | 0/51 (0%) | 0/54 (0%) | 1/49 (2%) | ||||||||
| Pyrexia | 1/28 (3.6%) | 4/53 (7.5%) | 5/56 (8.9%) | 11/55 (20%) | 0/27 (0%) | 2/51 (3.9%) | 0/54 (0%) | 0/49 (0%) | ||||||||
| Infections and infestations | ||||||||||||||||
| Gingivitis | 2/28 (7.1%) | 0/53 (0%) | 0/56 (0%) | 0/55 (0%) | 0/27 (0%) | 1/51 (2%) | 1/54 (1.9%) | 0/49 (0%) | ||||||||
| Nasopharyngitis | 3/28 (10.7%) | 2/53 (3.8%) | 2/56 (3.6%) | 1/55 (1.8%) | 0/27 (0%) | 5/51 (9.8%) | 1/54 (1.9%) | 1/49 (2%) | ||||||||
| Upper respiratory tract infection | 3/28 (10.7%) | 3/53 (5.7%) | 0/56 (0%) | 4/55 (7.3%) | 2/27 (7.4%) | 3/51 (5.9%) | 4/54 (7.4%) | 2/49 (4.1%) | ||||||||
| Metabolism and nutrition disorders | ||||||||||||||||
| Decreased appetite | 1/28 (3.6%) | 1/53 (1.9%) | 3/56 (5.4%) | 1/55 (1.8%) | 0/27 (0%) | 0/51 (0%) | 0/54 (0%) | 0/49 (0%) | ||||||||
| Musculoskeletal and connective tissue disorders | ||||||||||||||||
| Arthralgia | 0/28 (0%) | 3/53 (5.7%) | 3/56 (5.4%) | 10/55 (18.2%) | 0/27 (0%) | 2/51 (3.9%) | 0/54 (0%) | 0/49 (0%) | ||||||||
| Back pain | 0/28 (0%) | 2/53 (3.8%) | 4/56 (7.1%) | 2/55 (3.6%) | 2/27 (7.4%) | 2/51 (3.9%) | 0/54 (0%) | 1/49 (2%) | ||||||||
| Myalgia | 3/28 (10.7%) | 5/53 (9.4%) | 4/56 (7.1%) | 9/55 (16.4%) | 0/27 (0%) | 0/51 (0%) | 0/54 (0%) | 0/49 (0%) | ||||||||
| Pain in extremity | 0/28 (0%) | 2/53 (3.8%) | 3/56 (5.4%) | 1/55 (1.8%) | 0/27 (0%) | 0/51 (0%) | 0/54 (0%) | 0/49 (0%) | ||||||||
| Nervous system disorders | ||||||||||||||||
| Dizziness | 3/28 (10.7%) | 3/53 (5.7%) | 1/56 (1.8%) | 5/55 (9.1%) | 0/27 (0%) | 0/51 (0%) | 0/54 (0%) | 1/49 (2%) | ||||||||
| Headache | 5/28 (17.9%) | 4/53 (7.5%) | 10/56 (17.9%) | 12/55 (21.8%) | 0/27 (0%) | 2/51 (3.9%) | 0/54 (0%) | 1/49 (2%) | ||||||||
| Respiratory, thoracic and mediastinal disorders | ||||||||||||||||
| Cough | 0/28 (0%) | 3/53 (5.7%) | 0/56 (0%) | 2/55 (3.6%) | 2/27 (7.4%) | 2/51 (3.9%) | 1/54 (1.9%) | 3/49 (6.1%) | ||||||||
| Oropharyngeal pain | 1/28 (3.6%) | 5/53 (9.4%) | 1/56 (1.8%) | 1/55 (1.8%) | 1/27 (3.7%) | 0/51 (0%) | 2/54 (3.7%) | 0/49 (0%) | ||||||||
| Skin and subcutaneous tissue disorders | ||||||||||||||||
| Pruritus | 0/28 (0%) | 3/53 (5.7%) | 1/56 (1.8%) | 2/55 (3.6%) | 1/27 (3.7%) | 0/51 (0%) | 0/54 (0%) | 0/49 (0%) | ||||||||
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
After conclusion of the study and without prior written approval from Gilead, investigators in this study may communicate, orally present, or publish in scientific journals or other media only after the following conditions have been met: The results of the study in their entirety have been publicly disclosed by or with the consent of Gilead in an abstract, manuscript, or presentation form; or The study has been completed at all study sites for at least 2 years
Results Point of Contact
| Name/Title | Gilead Clinical Study Information Center |
|---|---|
| Organization | Gilead Sciences |
| Phone | 1-833-445-3230 (GILEAD-0) |
| GileadClinicalTrials@gilead.com |
Responsible Party:
Gilead Sciences
ClinicalTrials.gov Identifier:
NCT02579382
Other Study ID Numbers:
- GS-US-283-1062
- 2015-002017-30
First Posted:
Oct 19, 2015
Last Update Posted:
May 18, 2020
Last Verified:
May 1, 2020