Trial Outcomes & Findings for Exploratory fMRI Study on the Treatment for Impulsive Aggression in Children With ADHD (NCT NCT03638466)

NCT ID: NCT03638466

Last Updated: 2025-05-02

Results Overview

The primary endpoint was the aggression-related change in the whole brain in BOLD signal fMRI contrast in response to the PSAP task. BOLD fMRI contrast (neural activation) investigates brain activity by measuring the change in blood oxygenation. Change in brain activity was measured by a change in BOLD response in brain regions during the aggressive response relative to the monetary response, where the aggression was defined as the number of Option 2 presses (aggressive response) divided by the total number of button presses and the number of provocations. Change of aggression-related MRI signal was acquired at baseline and 4 weeks after SPN-810 treatment. A positive number represents an increase in activity. Region of interest is described by the location of the peak value and described by Montreal Neurological Institute (MNI) X, Y, Z coordinates. Data represent the post-treatment minus baseline change in BOLD contrast Aggressive Response\> Monetary Response.

Recruitment status

TERMINATED

Study phase

PHASE2

Target enrollment

7 participants

Primary outcome timeframe

Baseline/Visit 2 (Day -5) to Visit 5 (Day 28) for a total of 4 weeks.

Results posted on

2025-05-02

Participant Flow

A multi-center, double-blind, randomized (1:1), placebo-controlled, parallel-group, 2-arm study

Participant milestones

Participant milestones
Measure
Placebo
Subjects were randomized to receive Placebo twice each day, with or without food preferably every 12 hours, in addition to the stable dose of the optimized ADHD medication.
High Dose SPN-810 (36 mg)
Subjects were randomized to receive SPN-810 18 mg twice each day, with or without food preferably every 12 hours, in addition to the stable dose of the optimized ADHD medication.
Overall Study
STARTED
4
3
Overall Study
Randomized Population
4
3
Overall Study
Completed Population
4
2
Overall Study
COMPLETED
4
2
Overall Study
NOT COMPLETED
0
1

Reasons for withdrawal

Reasons for withdrawal
Measure
Placebo
Subjects were randomized to receive Placebo twice each day, with or without food preferably every 12 hours, in addition to the stable dose of the optimized ADHD medication.
High Dose SPN-810 (36 mg)
Subjects were randomized to receive SPN-810 18 mg twice each day, with or without food preferably every 12 hours, in addition to the stable dose of the optimized ADHD medication.
Overall Study
Early Termination
0
1

Baseline Characteristics

Exploratory fMRI Study on the Treatment for Impulsive Aggression in Children With ADHD

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure
Placebo
n=4 Participants
Subjects treated with Placebo
High Dose SPN-810 (36 mg)
n=3 Participants
Subjects treated with SPN-810
Total
n=7 Participants
Total of all reporting groups
Age, Categorical
<=18 years
4 Participants
n=5 Participants
3 Participants
n=7 Participants
7 Participants
n=5 Participants
Age, Categorical
Between 18 and 65 years
0 Participants
n=5 Participants
0 Participants
n=7 Participants
0 Participants
n=5 Participants
Age, Categorical
>=65 years
0 Participants
n=5 Participants
0 Participants
n=7 Participants
0 Participants
n=5 Participants
Age, Continuous
9.5 years
STANDARD_DEVIATION 1.29 • n=5 Participants
11.3 years
STANDARD_DEVIATION 1.15 • n=7 Participants
10.3 years
STANDARD_DEVIATION 1.50 • n=5 Participants
Sex: Female, Male
Female
0 Participants
n=5 Participants
2 Participants
n=7 Participants
2 Participants
n=5 Participants
Sex: Female, Male
Male
4 Participants
n=5 Participants
1 Participants
n=7 Participants
5 Participants
n=5 Participants
Ethnicity (NIH/OMB)
Hispanic or Latino
2 Participants
n=5 Participants
2 Participants
n=7 Participants
4 Participants
n=5 Participants
Ethnicity (NIH/OMB)
Not Hispanic or Latino
2 Participants
n=5 Participants
1 Participants
n=7 Participants
3 Participants
n=5 Participants
Ethnicity (NIH/OMB)
Unknown or Not Reported
0 Participants
n=5 Participants
0 Participants
n=7 Participants
0 Participants
n=5 Participants
Race (NIH/OMB)
American Indian or Alaska Native
0 Participants
n=5 Participants
0 Participants
n=7 Participants
0 Participants
n=5 Participants
Race (NIH/OMB)
Asian
0 Participants
n=5 Participants
0 Participants
n=7 Participants
0 Participants
n=5 Participants
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
0 Participants
n=5 Participants
0 Participants
n=7 Participants
0 Participants
n=5 Participants
Race (NIH/OMB)
Black or African American
2 Participants
n=5 Participants
1 Participants
n=7 Participants
3 Participants
n=5 Participants
Race (NIH/OMB)
White
2 Participants
n=5 Participants
1 Participants
n=7 Participants
3 Participants
n=5 Participants
Race (NIH/OMB)
More than one race
0 Participants
n=5 Participants
0 Participants
n=7 Participants
0 Participants
n=5 Participants
Race (NIH/OMB)
Unknown or Not Reported
0 Participants
n=5 Participants
1 Participants
n=7 Participants
1 Participants
n=5 Participants
Region of Enrollment
United States
4 participants
n=5 Participants
3 participants
n=7 Participants
7 participants
n=5 Participants
Vitiello Aggression Total Score
-3.5 units on a scale
STANDARD_DEVIATION 1.29 • n=5 Participants
-3.7 units on a scale
STANDARD_DEVIATION 1.53 • n=7 Participants
-3.6 units on a scale
STANDARD_DEVIATION 1.27 • n=5 Participants
Retrospective-Modified Overt Aggression Scale (R-MOAS) Total Score
102.5 units on a scale
STANDARD_DEVIATION 32.30 • n=5 Participants
57.0 units on a scale
STANDARD_DEVIATION 6.00 • n=7 Participants
83.0 units on a scale
STANDARD_DEVIATION 33.54 • n=5 Participants
Impulsive Aggression Measured by Clinical Global Impression - Severity Scale (CGI-S) Score
5.8 units on a scale
STANDARD_DEVIATION 0.96 • n=5 Participants
5.0 units on a scale
STANDARD_DEVIATION 1.41 • n=7 Participants
5.5 units on a scale
STANDARD_DEVIATION 1.05 • n=5 Participants

PRIMARY outcome

Timeframe: Baseline/Visit 2 (Day -5) to Visit 5 (Day 28) for a total of 4 weeks.

Population: Completed population included all subjects randomized, who had a Baseline imaging scan (including the anatomical scan) and post-treatment imaging scans.

The primary endpoint was the aggression-related change in the whole brain in BOLD signal fMRI contrast in response to the PSAP task. BOLD fMRI contrast (neural activation) investigates brain activity by measuring the change in blood oxygenation. Change in brain activity was measured by a change in BOLD response in brain regions during the aggressive response relative to the monetary response, where the aggression was defined as the number of Option 2 presses (aggressive response) divided by the total number of button presses and the number of provocations. Change of aggression-related MRI signal was acquired at baseline and 4 weeks after SPN-810 treatment. A positive number represents an increase in activity. Region of interest is described by the location of the peak value and described by Montreal Neurological Institute (MNI) X, Y, Z coordinates. Data represent the post-treatment minus baseline change in BOLD contrast Aggressive Response\> Monetary Response.

Outcome measures

Outcome measures
Measure
SPN-810 (36 mg) > Placebo
n=2 Participants
Increase over placebo BOLD response in subjects treated with high dose of SPN-810
Placebo > SPN-810 (36 mg)
n=4 Participants
Increase over high dose of SPN-810 BOLD response in subjects treated with placebo
Aggression-related Change in the Whole Brain in BOLD (Blood Oxygenation Level-dependent) Signal fMRI Contrast in Response to the PSAP Task
Medial Precuneus: Montreal Neurological Institute coordinates -33.5, 34.5, 47.5
128 Voxels
Interval 111.3 to 144.7
0 Voxels
Interval 0.0 to 0.0
Aggression-related Change in the Whole Brain in BOLD (Blood Oxygenation Level-dependent) Signal fMRI Contrast in Response to the PSAP Task
Right Postcentral Gyrus: Montreal Neurological Institute coordinates -29.5, 62.5, -4.5
110 Voxels
Interval 95.1 to 124.9
0 Voxels
Interval 0.0 to 0.0
Aggression-related Change in the Whole Brain in BOLD (Blood Oxygenation Level-dependent) Signal fMRI Contrast in Response to the PSAP Task
Right Insula Montreal Neurological Institute coordinates -39.5, -13.5, -0.5
0 Voxels
Interval 0.0 to 0.0
140 Voxels
Interval 116.4 to 163.6
Aggression-related Change in the Whole Brain in BOLD (Blood Oxygenation Level-dependent) Signal fMRI Contrast in Response to the PSAP Task
Left Postcentral Gyrus: Montreal Neurological Institute coordinates 30.5, 30.5, 51.5
0 Voxels
Interval 0.0 to 0.0
110 Voxels
Interval 95.1 to 124.9
Aggression-related Change in the Whole Brain in BOLD (Blood Oxygenation Level-dependent) Signal fMRI Contrast in Response to the PSAP Task
Inferior Occipital Gyrus/Cerebellum: Montreal Neurological Institute coordinates -29.5, 62.5, -4.5
353 Voxels
Interval 310.6 to 395.4
0 Voxels
Interval 0.0 to 0.0
Aggression-related Change in the Whole Brain in BOLD (Blood Oxygenation Level-dependent) Signal fMRI Contrast in Response to the PSAP Task
Right Fusiform Gyrus/Inferior Occipital Cortex: Montreal Neurological Institute 32.5, 52.5, 23.5
258 Voxels
Interval 223.1 to 292.9
0 Voxels
Interval 0.0 to 0.0
Aggression-related Change in the Whole Brain in BOLD (Blood Oxygenation Level-dependent) Signal fMRI Contrast in Response to the PSAP Task
Left Angular Gyrus (WM): Montreal Neurological Institute coordinates 4.5, 84.5, 35.5
173 Voxels
Interval 145.2 to 200.8
0 Voxels
Interval 0.0 to 0.0
Aggression-related Change in the Whole Brain in BOLD (Blood Oxygenation Level-dependent) Signal fMRI Contrast in Response to the PSAP Task
Left Cuneus: Montreal Neurological Institute coordinates -23.5, 96.5, 5.5
145 Voxels
Interval 124.6 to 165.4
0 Voxels
Interval 0.0 to 0.0
Aggression-related Change in the Whole Brain in BOLD (Blood Oxygenation Level-dependent) Signal fMRI Contrast in Response to the PSAP Task
Right Middle Occipital Gyrus: Montreal Neurological Institute coordinates -1.5, 64.5, 57.5
133 Voxels
Interval 114.2 to 151.8
0 Voxels
Interval 0.0 to 0.0
Aggression-related Change in the Whole Brain in BOLD (Blood Oxygenation Level-dependent) Signal fMRI Contrast in Response to the PSAP Task
Superior Medial Frontal Gyrus: Montreal Neurological Institute coordinates 2.5, -47.5, 39.5
0 Voxels
Interval 0.0 to 0.0
329 Voxels
Interval 288.6 to 369.4
Aggression-related Change in the Whole Brain in BOLD (Blood Oxygenation Level-dependent) Signal fMRI Contrast in Response to the PSAP Task
Right Cerebellum: Montreal Neurological Institute coordinates: -35.5, 72.5, -40.5
0 Voxels
Interval 0.0 to 0.0
175 Voxels
Interval 145.2 to 204.8
Aggression-related Change in the Whole Brain in BOLD (Blood Oxygenation Level-dependent) Signal fMRI Contrast in Response to the PSAP Task
Right Superior/Middle Frontal Gyrus: Montreal Neurological Institute coordinates -37.5, -33.5, 33.5
0 Voxels
Interval 0.0 to 0.0
164 Voxels
Interval 136.2 to 191.8
Aggression-related Change in the Whole Brain in BOLD (Blood Oxygenation Level-dependent) Signal fMRI Contrast in Response to the PSAP Task
Right Inferior Temporal Gyrus: Montreal Neurological Institute coordinates -41.5, -7.5, -46.5
0 Voxels
Interval 0.0 to 0.0
145 Voxels
Interval 124.6 to 165.4

PRIMARY outcome

Timeframe: Baseline/Visit 2 (Day -5) to Visit 5 (Day 28) for a total of 4 weeks.

Population: Completed population included all subjects randomized, who had a Baseline imaging scan (including the anatomical scan) and post-treatment imaging scans.

BOLD (blood oxygenation level-dependent) fMRI contrast (neural activation) investigates brain activity by measuring the change in blood oxygenation. It was collected during the PSAP behavioral task while playing the game: the participants play a computer game in which they can steal points (simulating an aggressive behavior) or have points stolen by the opponent (provocation event) by pressing Option 1, 2 or 3 on a keypad a set number of times to achieve a specific outcome. A positive number represents an increase in activity. The region of interest is described by the location of the peak value within that cluster and described by Montreal Neurological Institute (MNI) X, Y, and Z coordinates. Data represent the post-treatment minus baseline change in BOLD contrast Provocation Event \>Monetary Response.

Outcome measures

Outcome measures
Measure
SPN-810 (36 mg) > Placebo
n=2 Participants
Increase over placebo BOLD response in subjects treated with high dose of SPN-810
Placebo > SPN-810 (36 mg)
n=4 Participants
Increase over high dose of SPN-810 BOLD response in subjects treated with placebo
Provocation Event - Related Change in the Whole Brain in BOLD Signal fMRI Contrast in Response to the PSAP Task
Right Cerebellum: Montreal Neurological Institute coordinates: -23.5, 70.5, -24.5
0 Voxels
Interval 0.0 to 0.0
109 Voxels
Interval 94.4 to 123.6
Provocation Event - Related Change in the Whole Brain in BOLD Signal fMRI Contrast in Response to the PSAP Task
Right Postcentral Gyrus: Montreal Neurological Institute coordinates: -31.5, 30.5, 43.5
318 Voxels
Interval 276.3 to 359.7
0 Voxels
Interval 0.0 to 0.0
Provocation Event - Related Change in the Whole Brain in BOLD Signal fMRI Contrast in Response to the PSAP Task
Left Middle/Inferior Temporal Gyrus: Montreal Neurological Institute coordinates 52.5, 16.5, -24.5
137 Voxels
Interval 117.5 to 156.5
0 Voxels
Interval 0.0 to 0.0
Provocation Event - Related Change in the Whole Brain in BOLD Signal fMRI Contrast in Response to the PSAP Task
Medial Cerebellum: Montreal Neurological Institute coordinates: 12.5, 50.5 -32.5
0 Voxels
Interval 0.0 to 0.0
123 Voxels
Interval 104.1 to 141.9
Provocation Event - Related Change in the Whole Brain in BOLD Signal fMRI Contrast in Response to the PSAP Task
Left Inferior Frontal Gyrus: Montreal Neurological Institute coordinates: 42.5, -15.5, 19.5
0 Voxels
Interval 0.0 to 0.0
122 Voxels
Interval 105.0 to 139.0

PRIMARY outcome

Timeframe: Baseline/Visit 2 (Day -5) to Visit 5 (Day 28) for a total of 4 weeks.

Population: Completed population included all subjects randomized, who had a Baseline imaging scan (including the anatomical scan) and post-treatment imaging scans.

The Point Subtraction Aggression Paradigm (PSAP) is a behavioral aggression paradigm consisting of a computer game in which each participant plays against a computer to earn points. The subject can steal points (i.e., aggressive behavior) or have points stolen by the opponent (i.e., provocation). The subject can press 1 of 3 buttons on a keypad a set number of times. By pressing the button for Option 1, 100 times, the subject will earn a point; pressing the button for Option 2, 20 consecutive times is the "aggression" action that results in stealing a point from the opponent; pressing Option 3, 20 times protects the subject from the opponent's attempt to steal points (i.e., money). The aggression score is averaged across two sessions and calculated as the number of Option 2 button presses divided by the sum of total button presses and the number of provocation events received, with a range minimum = 1, maximum = 143. The higher scores reflect increased aggression.

Outcome measures

Outcome measures
Measure
SPN-810 (36 mg) > Placebo
n=4 Participants
Increase over placebo BOLD response in subjects treated with high dose of SPN-810
Placebo > SPN-810 (36 mg)
n=2 Participants
Increase over high dose of SPN-810 BOLD response in subjects treated with placebo
Effect of SPN-810 on the Aggressions Score
Baseline/Visit 2
8.43 score on a scale
Standard Deviation 9.22
10.23 score on a scale
Standard Deviation 6.21
Effect of SPN-810 on the Aggressions Score
Visit 5
9.26 score on a scale
Standard Deviation 5.50
4.02 score on a scale
Standard Deviation 2.60

SECONDARY outcome

Timeframe: Baseline/Visit 2 (Day -5) to Visit 5 (Day 28) for a total of 4 weeks.

Population: Completed population included all subjects randomized, who had a Baseline imaging scan (including the anatomical scan) and post-treatment imaging scans

GABA and Glutamate concentrations (mM) were measured in the anterior cingulate cortex using magnetic resonance spectroscopy (MRS). Data represent the change from Baseline (Visit 2) to Visit 5.

Outcome measures

Outcome measures
Measure
SPN-810 (36 mg) > Placebo
n=4 Participants
Increase over placebo BOLD response in subjects treated with high dose of SPN-810
Placebo > SPN-810 (36 mg)
n=2 Participants
Increase over high dose of SPN-810 BOLD response in subjects treated with placebo
Effect of SPN-810 on GABA and Glutamate Levels Using Magnetic Resonance Spectroscopy (MRS)
GABA (mM)
0.79 mM
Standard Deviation 0.26
0.75 mM
Standard Deviation 0.67
Effect of SPN-810 on GABA and Glutamate Levels Using Magnetic Resonance Spectroscopy (MRS)
Glutamate (mM)
0.78 mM
Standard Deviation 2.44
0.23 mM
Standard Deviation 1.91

OTHER_PRE_SPECIFIED outcome

Timeframe: From Visit 1 (Day -30) to two time points: Visit 4 (Day 21) and Visit 6 (Day 35).

Population: Completed population included all subjects randomized, who had a Baseline imaging scan (including the anatomical scan) and post-treatment imaging scans.

The Clinical Global Impression - Severity of Illness (CGI-S) is a single item clinician rating of clinician's assessment of the severity of IA behaviors. CGI-S was evaluated by the Investigator on a 7- point scale with 1=Normal, 2=Borderline ill, 3=Mildly ill, 4=Moderately ill, 5=Markedly ill, 6=Severely ill, and 7=Extremely ill. Data represent the change between Baseline (Visit 1/Day -30) and two time points: Visit 4 (Day 21) and Visit 6 (Day 35).

Outcome measures

Outcome measures
Measure
SPN-810 (36 mg) > Placebo
n=4 Participants
Increase over placebo BOLD response in subjects treated with high dose of SPN-810
Placebo > SPN-810 (36 mg)
n=2 Participants
Increase over high dose of SPN-810 BOLD response in subjects treated with placebo
Effect of SPN-810 on Impulsive Aggression Measured by the Clinical Global Impression-Severity (CGI-S) Scale
Visit 4
-1.25 score on a scale
Standard Deviation 1.5
-1.5 score on a scale
Standard Deviation 2.12
Effect of SPN-810 on Impulsive Aggression Measured by the Clinical Global Impression-Severity (CGI-S) Scale
Visit 6
-2.25 score on a scale
Standard Deviation 1.5
-1.5 score on a scale
Standard Deviation 2.12

OTHER_PRE_SPECIFIED outcome

Timeframe: Visit 4 (Day 21) and Visit 6 (Day 35), for a total of 2 weeks.

Population: Completed population included all subjects randomized, who had a Baseline imaging scan (including the anatomical scan) and post-treatment imaging scans.

The Clinical Global Impression - Improvement Scale (CGI-I) is an assessment of how much the patient's illness has improved or worsened relative to a baseline state at the beginning of treatment. CGI-I was evaluated by the Investigator on a 7-point scale with 1=very much improved, 2= much improved, 3= minimally improved, 4= no change, 5= minimally worse, 6= much worse, 7= very much worse.

Outcome measures

Outcome measures
Measure
SPN-810 (36 mg) > Placebo
n=4 Participants
Increase over placebo BOLD response in subjects treated with high dose of SPN-810
Placebo > SPN-810 (36 mg)
n=2 Participants
Increase over high dose of SPN-810 BOLD response in subjects treated with placebo
Effect of SPN-810 on Impulsive Aggression Measured by the Clinical Global Impression-Improvement (CGI-I) Scale
Visit 4
2.3 score on a scale
Standard Deviation 1.26
1.5 score on a scale
Standard Deviation 0.71
Effect of SPN-810 on Impulsive Aggression Measured by the Clinical Global Impression-Improvement (CGI-I) Scale
Visit 6
2.3 score on a scale
Standard Deviation 1.26
1.0 score on a scale
Standard Deviation 0.0

OTHER_PRE_SPECIFIED outcome

Timeframe: Visit 1 (Day -30) to Visit 4 (Day 21) and Visit 6 (Day 35).

Population: Completed population included all subjects randomized, who had a Baseline imaging scan (including the anatomical scan) and post-treatment imaging scans.

R-MOAS scale gauges the severity of aggressive behavior: the frequency of the 16 behaviors is rated over the past week in 4 areas (a-d). For each open question in each area, the parent rates the aggressive behaviors on a scale from 0 to 5 or more times. To each area corresponds a weighted category: 1(a), 4(b), 2(c) and 3(d). Therefore, the sum of each area yields a maximum weighted score of 20 (a), 120 (b), 60 (c) and 90 (c). The total score is the sum of the four area scores or 0-290, the higher the score, the more severe the aggressive behavior is. Data represent the change from baseline at each visit.

Outcome measures

Outcome measures
Measure
SPN-810 (36 mg) > Placebo
n=4 Participants
Increase over placebo BOLD response in subjects treated with high dose of SPN-810
Placebo > SPN-810 (36 mg)
n=2 Participants
Increase over high dose of SPN-810 BOLD response in subjects treated with placebo
Effect of SPN-810 on the Retrospective-Modified Overt Aggression Scale (R-MOAS) Score
Visit 4
-52.0 score on a scale
Standard Deviation 30.23
-43.0 score on a scale
Standard Deviation 2.83
Effect of SPN-810 on the Retrospective-Modified Overt Aggression Scale (R-MOAS) Score
Visit 6
-61.0 score on a scale
Standard Deviation 18.81
-39.5 score on a scale
Standard Deviation 24.75

Adverse Events

Placebo

Serious events: 0 serious events
Other events: 2 other events
Deaths: 0 deaths

High Dose SPN-810

Serious events: 0 serious events
Other events: 1 other events
Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure
Placebo
n=4 participants at risk
Subjects treated with Placebo
High Dose SPN-810
n=3 participants at risk
Subjects treated with 36 mg SPN-810
General disorders
Fatigue
25.0%
1/4 • Visit 3 (Day 1) to Visit 6 (Week5)-End of Study, a total of 5 weeks
Adverse events reporting pertains to the Safety Population which included all subjects randomized and who received at least 1 dose of study drug.
0.00%
0/3 • Visit 3 (Day 1) to Visit 6 (Week5)-End of Study, a total of 5 weeks
Adverse events reporting pertains to the Safety Population which included all subjects randomized and who received at least 1 dose of study drug.
Metabolism and nutrition disorders
Decrease appetite
50.0%
2/4 • Visit 3 (Day 1) to Visit 6 (Week5)-End of Study, a total of 5 weeks
Adverse events reporting pertains to the Safety Population which included all subjects randomized and who received at least 1 dose of study drug.
0.00%
0/3 • Visit 3 (Day 1) to Visit 6 (Week5)-End of Study, a total of 5 weeks
Adverse events reporting pertains to the Safety Population which included all subjects randomized and who received at least 1 dose of study drug.
Investigations
Blood Prolactin Increased
0.00%
0/4 • Visit 3 (Day 1) to Visit 6 (Week5)-End of Study, a total of 5 weeks
Adverse events reporting pertains to the Safety Population which included all subjects randomized and who received at least 1 dose of study drug.
33.3%
1/3 • Visit 3 (Day 1) to Visit 6 (Week5)-End of Study, a total of 5 weeks
Adverse events reporting pertains to the Safety Population which included all subjects randomized and who received at least 1 dose of study drug.

Additional Information

Gianpiera Ceresoli-Borroni Director Clinical Research

Supernus Pharmaceuticals

Phone: 3018382521

Results disclosure agreements

  • Principal investigator is a sponsor employee
  • Publication restrictions are in place