Trial Outcomes & Findings for A Multi-dose Study of ARC-520 in Patients With Hepatitis B 'e' Antigen (HBeAg) Negative, Chronic Hepatitis B Virus (HBV) Infection (NCT NCT02604199)
NCT ID: NCT02604199
Last Updated: 2026-01-13
Results Overview
Change From Baseline in log qHBsAg at Day 113 in response to multiple doses of ARC-520 versus placebo, using a a mixed effect model for repeated measures (MMRM). Includes parameter baseline as a continuous covariate, and treatment and visit as fixed factors, interaction of treatment and visit, and interaction of parameter baseline and visit.
TERMINATED
PHASE2
58 participants
Baseline, Day 113
2026-01-13
Participant Flow
Participant milestones
| Measure |
PBO Low Dose
0.9% normal saline, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period
|
PBO High Dose
0.9% normal saline, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period
|
ARC-520 Injection 1 mg/kg
Intravenous ARC-520 at 1.0 mg/kg, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period
|
ARC-520 Injection 2 mg/kg
Intravenous ARC-520 at 2.0 mg/kg, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period
|
|---|---|---|---|---|
|
Overall Study
STARTED
|
9
|
11
|
17
|
21
|
|
Overall Study
COMPLETED
|
9
|
8
|
17
|
18
|
|
Overall Study
NOT COMPLETED
|
0
|
3
|
0
|
3
|
Reasons for withdrawal
| Measure |
PBO Low Dose
0.9% normal saline, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period
|
PBO High Dose
0.9% normal saline, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period
|
ARC-520 Injection 1 mg/kg
Intravenous ARC-520 at 1.0 mg/kg, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period
|
ARC-520 Injection 2 mg/kg
Intravenous ARC-520 at 2.0 mg/kg, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period
|
|---|---|---|---|---|
|
Overall Study
Pregnancy
|
0
|
0
|
0
|
1
|
|
Overall Study
Study terminated by sponsor
|
0
|
2
|
0
|
2
|
|
Overall Study
Withdrawal by Subject
|
0
|
1
|
0
|
0
|
Baseline Characteristics
A Multi-dose Study of ARC-520 in Patients With Hepatitis B 'e' Antigen (HBeAg) Negative, Chronic Hepatitis B Virus (HBV) Infection
Baseline characteristics by cohort
| Measure |
PBO Low Dose
n=9 Participants
0.9% normal saline, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period
|
PBO High Dose
n=11 Participants
0.9% normal saline, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period
|
ARC-520 Injection 1 mg/kg
n=17 Participants
Intravenous ARC-520 at 1.0 mg/kg, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period
|
ARC-520 Injection 2 mg/kg
n=21 Participants
Intravenous ARC-520 at 2.0 mg/kg, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period
|
Total
n=58 Participants
Total of all reporting groups
|
|---|---|---|---|---|---|
|
Age, Continuous
|
46.2 years
STANDARD_DEVIATION 12.10 • n=9 Participants
|
48.7 years
STANDARD_DEVIATION 9.50 • n=6 Participants
|
45.0 years
STANDARD_DEVIATION 10.48 • n=9 Participants
|
45.7 years
STANDARD_DEVIATION 10.48 • n=205 Participants
|
46.2 years
STANDARD_DEVIATION 10.29 • n=16 Participants
|
|
Sex: Female, Male
Female
|
2 Participants
n=9 Participants
|
1 Participants
n=6 Participants
|
7 Participants
n=9 Participants
|
9 Participants
n=205 Participants
|
19 Participants
n=16 Participants
|
|
Sex: Female, Male
Male
|
7 Participants
n=9 Participants
|
10 Participants
n=6 Participants
|
10 Participants
n=9 Participants
|
12 Participants
n=205 Participants
|
39 Participants
n=16 Participants
|
PRIMARY outcome
Timeframe: Baseline, Day 113Population: Intent to treat population: all participants who received at least 1 dose of study drug and had valid qHBsAg values at baseline and at least one time point on or after the Day 15 visit.
Change From Baseline in log qHBsAg at Day 113 in response to multiple doses of ARC-520 versus placebo, using a a mixed effect model for repeated measures (MMRM). Includes parameter baseline as a continuous covariate, and treatment and visit as fixed factors, interaction of treatment and visit, and interaction of parameter baseline and visit.
Outcome measures
| Measure |
PBO High Dose
n=14 Participants
0.9% normal saline, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period
|
PBO Low Dose
n=15 Participants
0.9% normal saline, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period
|
ARC-520 Injection 2 mg/kg
n=15 Participants
Intravenous ARC-520 at 2.0 mg/kg, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period
|
ARC-520 Injection 2 mg/kg
Intravenous ARC-520 at 2.0 mg/kg, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period
|
|---|---|---|---|---|
|
Change From Baseline in Quantitative Hepatitis B Surface Antigen (Log qHBsAg) at Day 113
|
-0.157 log IU/mL
Standard Error 0.036
|
-0.070 log IU/mL
Standard Error 0.033
|
-0.379 log IU/mL
Standard Error 0.033
|
—
|
SECONDARY outcome
Timeframe: Baseline, Day 15, 29, 43, 57, 71, 85, 99Population: Intent to treat population: all participants who received at least 1 dose of study drug and had valid qHBsAg values at baseline and at least one time point on or after the Day 15 visit.
Change From Baseline in log qHBsAg at Day 113 in response to multiple doses of ARC-520 versus placebo, using a a mixed effect model for repeated measures (MMRM). Includes parameter baseline as a continuous covariate, and treatment and visit as fixed factors, interaction of treatment and visit, and interaction of parameter baseline and visit.
Outcome measures
| Measure |
PBO High Dose
n=15 Participants
0.9% normal saline, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period
|
PBO Low Dose
n=18 Participants
0.9% normal saline, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period
|
ARC-520 Injection 2 mg/kg
n=19 Participants
Intravenous ARC-520 at 2.0 mg/kg, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period
|
ARC-520 Injection 2 mg/kg
Intravenous ARC-520 at 2.0 mg/kg, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period
|
|---|---|---|---|---|
|
Change From Baseline in Quantitative Hepatitis B Surface Antigen (Log qHBsAg) Over Time
Day 57
|
3.072 log IU/mL
Standard Error 1.061
|
3.291 log IU/mL
Standard Error 0.705
|
2.329 log IU/mL
Standard Error 0.971
|
—
|
|
Change From Baseline in Quantitative Hepatitis B Surface Antigen (Log qHBsAg) Over Time
Day 15
|
3.084 log IU/mL
Standard Error 1.004
|
3.297 log IU/mL
Standard Error 0.712
|
2.506 log IU/mL
Standard Error 0.844
|
—
|
|
Change From Baseline in Quantitative Hepatitis B Surface Antigen (Log qHBsAg) Over Time
Day 29
|
3.098 log IU/mL
Standard Error 0.986
|
3.291 log IU/mL
Standard Error 0.694
|
2.503 log IU/mL
Standard Error 0.846
|
—
|
|
Change From Baseline in Quantitative Hepatitis B Surface Antigen (Log qHBsAg) Over Time
Day 43
|
3.016 log IU/mL
Standard Error 1.124
|
3.188 log IU/mL
Standard Error 0.712
|
2.509 log IU/mL
Standard Error 0.836
|
—
|
|
Change From Baseline in Quantitative Hepatitis B Surface Antigen (Log qHBsAg) Over Time
Day 71
|
3.051 log IU/mL
Standard Error 1.029
|
3.206 log IU/mL
Standard Error 0.663
|
2.301 log IU/mL
Standard Error 0.969
|
—
|
|
Change From Baseline in Quantitative Hepatitis B Surface Antigen (Log qHBsAg) Over Time
Day 85
|
2.907 log IU/mL
Standard Error 0.963
|
3.309 log IU/mL
Standard Error 0.736
|
2.366 log IU/mL
Standard Error 0.862
|
—
|
|
Change From Baseline in Quantitative Hepatitis B Surface Antigen (Log qHBsAg) Over Time
Day 99
|
2.938 log IU/mL
Standard Error 1.055
|
3.302 log IU/mL
Standard Error 0.700
|
2.360 log IU/mL
Standard Error 0.950
|
—
|
SECONDARY outcome
Timeframe: Through Day 169Population: Safety Population: all participants who received at least 1 dose of study treatment or placebo, and had at least 1 post-dose safety assessment.
An AE is any untoward medical occurrence which does not necessarily have a causal relationship with this treatment. An SAE is any AE that: results in death; is life-threatening; requires inpatient hospitalization or prolongation of an existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; or is a medically important event or reaction. A treatment emergent AE (TEAE) was defined as an AE that was not present prior to the first study medication administration and started at/after the time of initiation of administration of study medication, or an AE which was present prior to initiation of study medication administration, which increased in severity after study medication administration.
Outcome measures
| Measure |
PBO High Dose
n=11 Participants
0.9% normal saline, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period
|
PBO Low Dose
n=9 Participants
0.9% normal saline, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period
|
ARC-520 Injection 2 mg/kg
n=17 Participants
Intravenous ARC-520 at 2.0 mg/kg, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period
|
ARC-520 Injection 2 mg/kg
n=21 Participants
Intravenous ARC-520 at 2.0 mg/kg, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period
|
|---|---|---|---|---|
|
Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Deaths and Discontinuations Due to AEs
≥ 1 AE
|
5 Participants
|
4 Participants
|
6 Participants
|
12 Participants
|
|
Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Deaths and Discontinuations Due to AEs
≥ 1 TEAE
|
4 Participants
|
4 Participants
|
6 Participants
|
12 Participants
|
|
Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Deaths and Discontinuations Due to AEs
≥ 1 Serious TEAE
|
0 Participants
|
0 Participants
|
2 Participants
|
1 Participants
|
|
Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Deaths and Discontinuations Due to AEs
Deaths
|
0 Participants
|
0 Participants
|
0 Participants
|
0 Participants
|
|
Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Deaths and Discontinuations Due to AEs
≥ 1 TEAE Leading to Study Discontinuation
|
0 Participants
|
0 Participants
|
0 Participants
|
0 Participants
|
|
Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Deaths and Discontinuations Due to AEs
≥ 1 TEAE Leading to Treatment Discontinuation
|
0 Participants
|
0 Participants
|
0 Participants
|
0 Participants
|
SECONDARY outcome
Timeframe: Through 48 hours post-dosing on Day 1 and Day 85Population: Due to the early suspension and termination of the study, all pharmacokinetic analyses were removed from the initial statistical analysis plan for this study. No collected samples were analyzed and all were destroyed.
Outcome measures
Outcome data not reported
SECONDARY outcome
Timeframe: Through 48 hours post-dosing on Day 1 and Day 85Population: Due to the early suspension and termination of the study, all pharmacokinetic analyses were removed from the initial statistical analysis plan for this study. No collected samples were analyzed and all were destroyed.
Outcome measures
Outcome data not reported
SECONDARY outcome
Timeframe: Through 48 hours post-dosing on Day 1 and Day 85Population: Due to the early suspension and termination of the study, all pharmacokinetic analyses were removed from the initial statistical analysis plan for this study. No collected samples were analyzed and all were destroyed.
Outcome measures
Outcome data not reported
SECONDARY outcome
Timeframe: Through 48 hours post-dosing on Day 1 and Day 85Population: Due to the early suspension and termination of the study, all pharmacokinetic analyses were removed from the initial statistical analysis plan for this study. No collected samples were analyzed and all were destroyed.
Outcome measures
Outcome data not reported
SECONDARY outcome
Timeframe: Through 48 hours post-dosing on Day 1 and Day 85Population: Due to the early suspension and termination of the study, all pharmacokinetic analyses were removed from the initial statistical analysis plan for this study. No collected samples were analyzed and all were destroyed.
Outcome measures
Outcome data not reported
SECONDARY outcome
Timeframe: Through 48 hours post-dosing on Day 1 and Day 85Population: Due to the early suspension and termination of the study, all pharmacokinetic analyses were removed from the initial statistical analysis plan for this study. No collected samples were analyzed and all were destroyed.
Outcome measures
Outcome data not reported
SECONDARY outcome
Timeframe: Through 48 hours post-dosing on Day 1 and Day 85Population: Due to the early suspension and termination of the study, all pharmacokinetic analyses were removed from the initial statistical analysis plan for this study. No collected samples were analyzed and all were destroyed.
Outcome measures
Outcome data not reported
SECONDARY outcome
Timeframe: Through 48 hours post-dosing on Day 1 and Day 85Population: Due to the early suspension and termination of the study, all pharmacokinetic analyses were removed from the initial statistical analysis plan for this study. No collected samples were analyzed and all were destroyed.
Outcome measures
Outcome data not reported
Adverse Events
PBO Low Dose
PBO High Dose
ARC-520 Injection 1 mg/kg
ARC-520 Injection 2 mg/kg
Serious adverse events
| Measure |
PBO Low Dose
n=9 participants at risk
0.9% normal saline, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period
|
PBO High Dose
n=11 participants at risk
0.9% normal saline, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period
|
ARC-520 Injection 1 mg/kg
n=17 participants at risk
Intravenous ARC-520 at 1.0 mg/kg, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period
|
ARC-520 Injection 2 mg/kg
n=21 participants at risk
Intravenous ARC-520 at 2.0 mg/kg, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period
|
|---|---|---|---|---|
|
General disorders
Pyrexia
|
0.00%
0/9 • Through Day 169
|
0.00%
0/11 • Through Day 169
|
5.9%
1/17 • Through Day 169
|
4.8%
1/21 • Through Day 169
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cholangiocarcinoma
|
0.00%
0/9 • Through Day 169
|
0.00%
0/11 • Through Day 169
|
5.9%
1/17 • Through Day 169
|
0.00%
0/21 • Through Day 169
|
Other adverse events
| Measure |
PBO Low Dose
n=9 participants at risk
0.9% normal saline, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period
|
PBO High Dose
n=11 participants at risk
0.9% normal saline, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period
|
ARC-520 Injection 1 mg/kg
n=17 participants at risk
Intravenous ARC-520 at 1.0 mg/kg, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period
|
ARC-520 Injection 2 mg/kg
n=21 participants at risk
Intravenous ARC-520 at 2.0 mg/kg, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period
|
|---|---|---|---|---|
|
General disorders
Fatigue
|
0.00%
0/9 • Through Day 169
|
0.00%
0/11 • Through Day 169
|
5.9%
1/17 • Through Day 169
|
9.5%
2/21 • Through Day 169
|
|
General disorders
Influenza like illness
|
0.00%
0/9 • Through Day 169
|
0.00%
0/11 • Through Day 169
|
5.9%
1/17 • Through Day 169
|
4.8%
1/21 • Through Day 169
|
|
General disorders
Malaise
|
11.1%
1/9 • Through Day 169
|
0.00%
0/11 • Through Day 169
|
0.00%
0/17 • Through Day 169
|
4.8%
1/21 • Through Day 169
|
|
General disorders
Pyrexia
|
0.00%
0/9 • Through Day 169
|
0.00%
0/11 • Through Day 169
|
5.9%
1/17 • Through Day 169
|
9.5%
2/21 • Through Day 169
|
|
Infections and infestations
Nasopharyngitis
|
0.00%
0/9 • Through Day 169
|
9.1%
1/11 • Through Day 169
|
0.00%
0/17 • Through Day 169
|
4.8%
1/21 • Through Day 169
|
|
Infections and infestations
Tonsillitis
|
0.00%
0/9 • Through Day 169
|
0.00%
0/11 • Through Day 169
|
5.9%
1/17 • Through Day 169
|
0.00%
0/21 • Through Day 169
|
|
Infections and infestations
Upper respiratory tract infection
|
11.1%
1/9 • Through Day 169
|
9.1%
1/11 • Through Day 169
|
5.9%
1/17 • Through Day 169
|
14.3%
3/21 • Through Day 169
|
|
Investigations
Aspartate aminotransferase increased
|
11.1%
1/9 • Through Day 169
|
0.00%
0/11 • Through Day 169
|
0.00%
0/17 • Through Day 169
|
0.00%
0/21 • Through Day 169
|
|
Investigations
Blood cholesterol increased
|
0.00%
0/9 • Through Day 169
|
0.00%
0/11 • Through Day 169
|
5.9%
1/17 • Through Day 169
|
0.00%
0/21 • Through Day 169
|
|
Investigations
Blood creatine phosphokinase increased
|
11.1%
1/9 • Through Day 169
|
0.00%
0/11 • Through Day 169
|
0.00%
0/17 • Through Day 169
|
0.00%
0/21 • Through Day 169
|
|
Musculoskeletal and connective tissue disorders
Arthralgia
|
11.1%
1/9 • Through Day 169
|
0.00%
0/11 • Through Day 169
|
0.00%
0/17 • Through Day 169
|
0.00%
0/21 • Through Day 169
|
|
Musculoskeletal and connective tissue disorders
Myalgia
|
0.00%
0/9 • Through Day 169
|
0.00%
0/11 • Through Day 169
|
5.9%
1/17 • Through Day 169
|
0.00%
0/21 • Through Day 169
|
|
Nervous system disorders
Headache
|
0.00%
0/9 • Through Day 169
|
0.00%
0/11 • Through Day 169
|
5.9%
1/17 • Through Day 169
|
4.8%
1/21 • Through Day 169
|
|
Nervous system disorders
Lethargy
|
11.1%
1/9 • Through Day 169
|
0.00%
0/11 • Through Day 169
|
0.00%
0/17 • Through Day 169
|
0.00%
0/21 • Through Day 169
|
|
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain
|
0.00%
0/9 • Through Day 169
|
9.1%
1/11 • Through Day 169
|
0.00%
0/17 • Through Day 169
|
0.00%
0/21 • Through Day 169
|
|
Skin and subcutaneous tissue disorders
Pruritus
|
0.00%
0/9 • Through Day 169
|
9.1%
1/11 • Through Day 169
|
0.00%
0/17 • Through Day 169
|
0.00%
0/21 • Through Day 169
|
|
Skin and subcutaneous tissue disorders
Rash
|
0.00%
0/9 • Through Day 169
|
0.00%
0/11 • Through Day 169
|
5.9%
1/17 • Through Day 169
|
0.00%
0/21 • Through Day 169
|
|
Vascular disorders
Hypotension
|
11.1%
1/9 • Through Day 169
|
0.00%
0/11 • Through Day 169
|
0.00%
0/17 • Through Day 169
|
0.00%
0/21 • Through Day 169
|
|
General disorders
Chest discomfort
|
0.00%
0/9 • Through Day 169
|
9.1%
1/11 • Through Day 169
|
0.00%
0/17 • Through Day 169
|
4.8%
1/21 • Through Day 169
|
|
General disorders
Chills
|
0.00%
0/9 • Through Day 169
|
0.00%
0/11 • Through Day 169
|
5.9%
1/17 • Through Day 169
|
0.00%
0/21 • Through Day 169
|
|
Cardiac disorders
Sinus bradycardia
|
11.1%
1/9 • Through Day 169
|
0.00%
0/11 • Through Day 169
|
0.00%
0/17 • Through Day 169
|
0.00%
0/21 • Through Day 169
|
|
Gastrointestinal disorders
Abdominal pain upper
|
11.1%
1/9 • Through Day 169
|
0.00%
0/11 • Through Day 169
|
0.00%
0/17 • Through Day 169
|
0.00%
0/21 • Through Day 169
|
|
Gastrointestinal disorders
Diarrhoea
|
11.1%
1/9 • Through Day 169
|
0.00%
0/11 • Through Day 169
|
0.00%
0/17 • Through Day 169
|
0.00%
0/21 • Through Day 169
|
|
Gastrointestinal disorders
Toothache
|
0.00%
0/9 • Through Day 169
|
0.00%
0/11 • Through Day 169
|
5.9%
1/17 • Through Day 169
|
0.00%
0/21 • Through Day 169
|
Additional Information
Chief Operating Officer
Arrowhead Pharmaceuticals, Inc.
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place