Trial Outcomes & Findings for Reducing Weight Gain and Improving Metabolic Function in Children Being Treated With Antipsychotics (NCT NCT00806234)

NCT ID: NCT00806234

Last Updated: 2017-04-25

Results Overview

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

127 participants

Primary outcome timeframe

Change from baseline to 24 weeks

Results posted on

2017-04-25

Participant Flow

Participant milestones

Participant milestones
Measure	Healthy Lifestyle Information Participants will continue on current antipsychotic medication. Olanzapine, quetiapine, risperidone, ziprasidone, aripiprazole, asenapine, iloperidone, lurasidone, paliperidone, or olanzapine/fluoxetine: Current antipsychotic medication will be continued throughout the treatment period, with changes in dose only made as clinically indicated	Switch Treatment + Healthy Lifestyle Instruction Participants will undergo a staggered switch from current antipsychotic medication to aripiprazole or perphenazine. Aripiprazole or Perphenazine: Baseline second generation antipsychotic (SGA) treatment will be gradually decreased and discontinued over 8 weeks while treatment with aripiprazole or perphenazine will be increased to effective levels.	Metformin Treatment + Healthy Lifestyle Instruction Participants will add metformin to current antipsychotic medication treatment. Metformin: Metformin treatment will be added to current SGA treatment, with dosing based on participant weight and increased according to a preset titration schedule unless side effects interfere.
Overall Study STARTED	47	31	49
Overall Study COMPLETED	34	19	37
Overall Study NOT COMPLETED	13	12	12

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Reducing Weight Gain and Improving Metabolic Function in Children Being Treated With Antipsychotics

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Healthy Lifestyle Information n=47 Participants Participants will continue on current antipsychotic medication. Olanzapine, quetiapine, risperidone, ziprasidone, aripiprazole, asenapine, iloperidone, lurasidone, paliperidone, or olanzapine/fluoxetine: Current antipsychotic medication will be continued throughout the treatment period, with changes in dose only made as clinically indicated	Switch Treatment + Healthy Lifestyle Instruction n=31 Participants Participants will undergo a staggered switch from current antipsychotic medication to aripiprazole or perphenazine. Aripiprazole or Perphenazine: Baseline second generation antipsychotic (SGA) treatment will be gradually decreased and discontinued over 8 weeks while treatment with aripiprazole or perphenazine will be increased to effective levels.	Metformin Treatment + Healthy Lifestyle Instruction n=49 Participants Participants will add metformin to current antipsychotic medication treatment. Metformin: Metformin treatment will be added to current SGA treatment, with dosing based on participant weight and increased according to a preset titration schedule unless side effects interfere.	Total n=127 Participants Total of all reporting groups
Age, Categorical <=18 years	41 Participants n=5 Participants	26 Participants n=7 Participants	45 Participants n=5 Participants	112 Participants n=4 Participants
Age, Categorical Between 18 and 65 years	6 Participants n=5 Participants	5 Participants n=7 Participants	4 Participants n=5 Participants	15 Participants n=4 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Sex: Female, Male Female	17 Participants n=5 Participants	10 Participants n=7 Participants	18 Participants n=5 Participants	45 Participants n=4 Participants
Sex: Female, Male Male	30 Participants n=5 Participants	21 Participants n=7 Participants	31 Participants n=5 Participants	82 Participants n=4 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	5 Participants n=5 Participants	4 Participants n=7 Participants	7 Participants n=5 Participants	16 Participants n=4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	42 Participants n=5 Participants	27 Participants n=7 Participants	42 Participants n=5 Participants	111 Participants n=4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 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	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	13 Participants n=5 Participants	9 Participants n=7 Participants	14 Participants n=5 Participants	36 Participants n=4 Participants
Race (NIH/OMB) White	25 Participants n=5 Participants	16 Participants n=7 Participants	26 Participants n=5 Participants	67 Participants n=4 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	9 Participants n=5 Participants	6 Participants n=7 Participants	9 Participants n=5 Participants	24 Participants n=4 Participants

PRIMARY outcome

Timeframe: Change from baseline to 24 weeks

Outcome measures

Outcome measures
Measure	Healthy Lifestyle Information n=44 Participants Participants will continue on current antipsychotic medication. Olanzapine, quetiapine, risperidone, ziprasidone, aripiprazole, asenapine, iloperidone, lurasidone, paliperidone, or olanzapine/fluoxetine: Current antipsychotic medication will be continued throughout the treatment period, with changes in dose only made as clinically indicated	Switch Treatment + Healthy Lifestyle Instruction n=30 Participants Participants will undergo a staggered switch from current antipsychotic medication to aripiprazole or perphenazine. Aripiprazole or Perphenazine: Baseline second generation antipsychotic (SGA) treatment will be gradually decreased and discontinued over 8 weeks while treatment with aripiprazole or perphenazine will be increased to effective levels.	Metformin Treatment + Healthy Lifestyle Instruction n=47 Participants Participants will add metformin to current antipsychotic medication treatment. Metformin: Metformin treatment will be added to current SGA treatment, with dosing based on participant weight and increased according to a preset titration schedule unless side effects interfere.
Body Mass Index (BMI) Z-score Change	0.040 Z Score Standard Error 0.029	-0.112 Z Score Standard Error 0.037	-0.088 Z Score Standard Error 0.028

SECONDARY outcome

Timeframe: Change from baseline to 24 weeks

Outcome measures

Outcome measures
Measure	Healthy Lifestyle Information n=44 Participants Participants will continue on current antipsychotic medication. Olanzapine, quetiapine, risperidone, ziprasidone, aripiprazole, asenapine, iloperidone, lurasidone, paliperidone, or olanzapine/fluoxetine: Current antipsychotic medication will be continued throughout the treatment period, with changes in dose only made as clinically indicated	Switch Treatment + Healthy Lifestyle Instruction n=30 Participants Participants will undergo a staggered switch from current antipsychotic medication to aripiprazole or perphenazine. Aripiprazole or Perphenazine: Baseline second generation antipsychotic (SGA) treatment will be gradually decreased and discontinued over 8 weeks while treatment with aripiprazole or perphenazine will be increased to effective levels.	Metformin Treatment + Healthy Lifestyle Instruction n=47 Participants Participants will add metformin to current antipsychotic medication treatment. Metformin: Metformin treatment will be added to current SGA treatment, with dosing based on participant weight and increased according to a preset titration schedule unless side effects interfere.
Change in Whole Body Insulin Sensitivity Index	0.74 mU/L Standard Error 0.82	0.42 mU/L Standard Error 0.91	-0.34 mU/L Standard Error 0.65

SECONDARY outcome

Timeframe: Change from baseline to 24 weeks

Outcome measures

Outcome measures
Measure	Healthy Lifestyle Information n=44 Participants Participants will continue on current antipsychotic medication. Olanzapine, quetiapine, risperidone, ziprasidone, aripiprazole, asenapine, iloperidone, lurasidone, paliperidone, or olanzapine/fluoxetine: Current antipsychotic medication will be continued throughout the treatment period, with changes in dose only made as clinically indicated	Switch Treatment + Healthy Lifestyle Instruction n=30 Participants Participants will undergo a staggered switch from current antipsychotic medication to aripiprazole or perphenazine. Aripiprazole or Perphenazine: Baseline second generation antipsychotic (SGA) treatment will be gradually decreased and discontinued over 8 weeks while treatment with aripiprazole or perphenazine will be increased to effective levels.	Metformin Treatment + Healthy Lifestyle Instruction n=47 Participants Participants will add metformin to current antipsychotic medication treatment. Metformin: Metformin treatment will be added to current SGA treatment, with dosing based on participant weight and increased according to a preset titration schedule unless side effects interfere.
Triglyceride Levels	0.2 mg/dL Standard Error 9.1	16.6 mg/dL Standard Error 12.0	14.7 mg/dL Standard Error 8.7

SECONDARY outcome

Timeframe: From Baseline to Week 24

Outcome measures

Outcome measures
Measure	Healthy Lifestyle Information n=44 Participants Participants will continue on current antipsychotic medication. Olanzapine, quetiapine, risperidone, ziprasidone, aripiprazole, asenapine, iloperidone, lurasidone, paliperidone, or olanzapine/fluoxetine: Current antipsychotic medication will be continued throughout the treatment period, with changes in dose only made as clinically indicated	Switch Treatment + Healthy Lifestyle Instruction n=30 Participants Participants will undergo a staggered switch from current antipsychotic medication to aripiprazole or perphenazine. Aripiprazole or Perphenazine: Baseline second generation antipsychotic (SGA) treatment will be gradually decreased and discontinued over 8 weeks while treatment with aripiprazole or perphenazine will be increased to effective levels.	Metformin Treatment + Healthy Lifestyle Instruction n=47 Participants Participants will add metformin to current antipsychotic medication treatment. Metformin: Metformin treatment will be added to current SGA treatment, with dosing based on participant weight and increased according to a preset titration schedule unless side effects interfere.
Change in Low Density Lipoprotein (LDL) Cholesterol Level	3.6 mg/dL Standard Error 4.2	-8.1 mg/dL Standard Error 5.4	-4.1 mg/dL Standard Error 3.9

Adverse Events

Healthy Lifestyle Information

Serious events: 1 serious events

Other events: 45 other events

Deaths: 0 deaths

Switch Treatment + Healthy Lifestyle Instruction

Serious events: 5 serious events

Other events: 30 other events

Deaths: 0 deaths

Metformin Treatment + Healthy Lifestyle Instruction

Serious events: 3 serious events

Other events: 47 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Healthy Lifestyle Information n=45 participants at risk Participants will continue on current antipsychotic medication. Olanzapine, quetiapine, risperidone, ziprasidone, aripiprazole, asenapine, iloperidone, lurasidone, paliperidone, or olanzapine/fluoxetine: Current antipsychotic medication will be continued throughout the treatment period, with changes in dose only made as clinically indicated	Switch Treatment + Healthy Lifestyle Instruction n=30 participants at risk Participants will undergo a staggered switch from current antipsychotic medication to aripiprazole or perphenazine. Aripiprazole or Perphenazine: Baseline second generation antipsychotic (SGA) treatment will be gradually decreased and discontinued over 8 weeks while treatment with aripiprazole or perphenazine will be increased to effective levels.	Metformin Treatment + Healthy Lifestyle Instruction n=47 participants at risk Participants will add metformin to current antipsychotic medication treatment. Metformin: Metformin treatment will be added to current SGA treatment, with dosing based on participant weight and increased according to a preset titration schedule unless side effects interfere.
Surgical and medical procedures Femur Fracture	2.2% 1/45 • Number of events 1 See the correct numbers for the 3 populations below. We had to exclude 5 participants (CONTROL = 2, METFORMIN = 2, SWITCH = 1). 1. Randomized population: Control - 47 Metformin - 49 Switch - 31 Aripiprazole - 13 Molindone - 1 Perphenazine - 17 2. Safety population: Control - 45 Metformin - 47 Switch - 30 Aripiprazole - 12 Molindone - 1 Perphenazine - 17 3. Efficacy population : Control - 44 Metformin - 47 Switch - 30 Aripiprazole - 12 Molindone - 1 Perphenazine - 17	0.00% 0/30 See the correct numbers for the 3 populations below. We had to exclude 5 participants (CONTROL = 2, METFORMIN = 2, SWITCH = 1). 1. Randomized population: Control - 47 Metformin - 49 Switch - 31 Aripiprazole - 13 Molindone - 1 Perphenazine - 17 2. Safety population: Control - 45 Metformin - 47 Switch - 30 Aripiprazole - 12 Molindone - 1 Perphenazine - 17 3. Efficacy population : Control - 44 Metformin - 47 Switch - 30 Aripiprazole - 12 Molindone - 1 Perphenazine - 17	0.00% 0/47 See the correct numbers for the 3 populations below. We had to exclude 5 participants (CONTROL = 2, METFORMIN = 2, SWITCH = 1). 1. Randomized population: Control - 47 Metformin - 49 Switch - 31 Aripiprazole - 13 Molindone - 1 Perphenazine - 17 2. Safety population: Control - 45 Metformin - 47 Switch - 30 Aripiprazole - 12 Molindone - 1 Perphenazine - 17 3. Efficacy population : Control - 44 Metformin - 47 Switch - 30 Aripiprazole - 12 Molindone - 1 Perphenazine - 17
Psychiatric disorders Aggression	0.00% 0/45 See the correct numbers for the 3 populations below. We had to exclude 5 participants (CONTROL = 2, METFORMIN = 2, SWITCH = 1). 1. Randomized population: Control - 47 Metformin - 49 Switch - 31 Aripiprazole - 13 Molindone - 1 Perphenazine - 17 2. Safety population: Control - 45 Metformin - 47 Switch - 30 Aripiprazole - 12 Molindone - 1 Perphenazine - 17 3. Efficacy population : Control - 44 Metformin - 47 Switch - 30 Aripiprazole - 12 Molindone - 1 Perphenazine - 17	3.3% 1/30 • Number of events 1 See the correct numbers for the 3 populations below. We had to exclude 5 participants (CONTROL = 2, METFORMIN = 2, SWITCH = 1). 1. Randomized population: Control - 47 Metformin - 49 Switch - 31 Aripiprazole - 13 Molindone - 1 Perphenazine - 17 2. Safety population: Control - 45 Metformin - 47 Switch - 30 Aripiprazole - 12 Molindone - 1 Perphenazine - 17 3. Efficacy population : Control - 44 Metformin - 47 Switch - 30 Aripiprazole - 12 Molindone - 1 Perphenazine - 17	0.00% 0/47 See the correct numbers for the 3 populations below. We had to exclude 5 participants (CONTROL = 2, METFORMIN = 2, SWITCH = 1). 1. Randomized population: Control - 47 Metformin - 49 Switch - 31 Aripiprazole - 13 Molindone - 1 Perphenazine - 17 2. Safety population: Control - 45 Metformin - 47 Switch - 30 Aripiprazole - 12 Molindone - 1 Perphenazine - 17 3. Efficacy population : Control - 44 Metformin - 47 Switch - 30 Aripiprazole - 12 Molindone - 1 Perphenazine - 17
Psychiatric disorders Hallucinations	0.00% 0/45 See the correct numbers for the 3 populations below. We had to exclude 5 participants (CONTROL = 2, METFORMIN = 2, SWITCH = 1). 1. Randomized population: Control - 47 Metformin - 49 Switch - 31 Aripiprazole - 13 Molindone - 1 Perphenazine - 17 2. Safety population: Control - 45 Metformin - 47 Switch - 30 Aripiprazole - 12 Molindone - 1 Perphenazine - 17 3. Efficacy population : Control - 44 Metformin - 47 Switch - 30 Aripiprazole - 12 Molindone - 1 Perphenazine - 17	3.3% 1/30 • Number of events 1 See the correct numbers for the 3 populations below. We had to exclude 5 participants (CONTROL = 2, METFORMIN = 2, SWITCH = 1). 1. Randomized population: Control - 47 Metformin - 49 Switch - 31 Aripiprazole - 13 Molindone - 1 Perphenazine - 17 2. Safety population: Control - 45 Metformin - 47 Switch - 30 Aripiprazole - 12 Molindone - 1 Perphenazine - 17 3. Efficacy population : Control - 44 Metformin - 47 Switch - 30 Aripiprazole - 12 Molindone - 1 Perphenazine - 17	0.00% 0/47 See the correct numbers for the 3 populations below. We had to exclude 5 participants (CONTROL = 2, METFORMIN = 2, SWITCH = 1). 1. Randomized population: Control - 47 Metformin - 49 Switch - 31 Aripiprazole - 13 Molindone - 1 Perphenazine - 17 2. Safety population: Control - 45 Metformin - 47 Switch - 30 Aripiprazole - 12 Molindone - 1 Perphenazine - 17 3. Efficacy population : Control - 44 Metformin - 47 Switch - 30 Aripiprazole - 12 Molindone - 1 Perphenazine - 17
Psychiatric disorders Suicidal ideation	0.00% 0/45 See the correct numbers for the 3 populations below. We had to exclude 5 participants (CONTROL = 2, METFORMIN = 2, SWITCH = 1). 1. Randomized population: Control - 47 Metformin - 49 Switch - 31 Aripiprazole - 13 Molindone - 1 Perphenazine - 17 2. Safety population: Control - 45 Metformin - 47 Switch - 30 Aripiprazole - 12 Molindone - 1 Perphenazine - 17 3. Efficacy population : Control - 44 Metformin - 47 Switch - 30 Aripiprazole - 12 Molindone - 1 Perphenazine - 17	6.7% 2/30 • Number of events 2 See the correct numbers for the 3 populations below. We had to exclude 5 participants (CONTROL = 2, METFORMIN = 2, SWITCH = 1). 1. Randomized population: Control - 47 Metformin - 49 Switch - 31 Aripiprazole - 13 Molindone - 1 Perphenazine - 17 2. Safety population: Control - 45 Metformin - 47 Switch - 30 Aripiprazole - 12 Molindone - 1 Perphenazine - 17 3. Efficacy population : Control - 44 Metformin - 47 Switch - 30 Aripiprazole - 12 Molindone - 1 Perphenazine - 17	0.00% 0/47 See the correct numbers for the 3 populations below. We had to exclude 5 participants (CONTROL = 2, METFORMIN = 2, SWITCH = 1). 1. Randomized population: Control - 47 Metformin - 49 Switch - 31 Aripiprazole - 13 Molindone - 1 Perphenazine - 17 2. Safety population: Control - 45 Metformin - 47 Switch - 30 Aripiprazole - 12 Molindone - 1 Perphenazine - 17 3. Efficacy population : Control - 44 Metformin - 47 Switch - 30 Aripiprazole - 12 Molindone - 1 Perphenazine - 17
Respiratory, thoracic and mediastinal disorders Asthma attack	0.00% 0/45 See the correct numbers for the 3 populations below. We had to exclude 5 participants (CONTROL = 2, METFORMIN = 2, SWITCH = 1). 1. Randomized population: Control - 47 Metformin - 49 Switch - 31 Aripiprazole - 13 Molindone - 1 Perphenazine - 17 2. Safety population: Control - 45 Metformin - 47 Switch - 30 Aripiprazole - 12 Molindone - 1 Perphenazine - 17 3. Efficacy population : Control - 44 Metformin - 47 Switch - 30 Aripiprazole - 12 Molindone - 1 Perphenazine - 17	0.00% 0/30 See the correct numbers for the 3 populations below. We had to exclude 5 participants (CONTROL = 2, METFORMIN = 2, SWITCH = 1). 1. Randomized population: Control - 47 Metformin - 49 Switch - 31 Aripiprazole - 13 Molindone - 1 Perphenazine - 17 2. Safety population: Control - 45 Metformin - 47 Switch - 30 Aripiprazole - 12 Molindone - 1 Perphenazine - 17 3. Efficacy population : Control - 44 Metformin - 47 Switch - 30 Aripiprazole - 12 Molindone - 1 Perphenazine - 17	2.1% 1/47 • Number of events 1 See the correct numbers for the 3 populations below. We had to exclude 5 participants (CONTROL = 2, METFORMIN = 2, SWITCH = 1). 1. Randomized population: Control - 47 Metformin - 49 Switch - 31 Aripiprazole - 13 Molindone - 1 Perphenazine - 17 2. Safety population: Control - 45 Metformin - 47 Switch - 30 Aripiprazole - 12 Molindone - 1 Perphenazine - 17 3. Efficacy population : Control - 44 Metformin - 47 Switch - 30 Aripiprazole - 12 Molindone - 1 Perphenazine - 17
Gastrointestinal disorders Appendicitis	0.00% 0/45 See the correct numbers for the 3 populations below. We had to exclude 5 participants (CONTROL = 2, METFORMIN = 2, SWITCH = 1). 1. Randomized population: Control - 47 Metformin - 49 Switch - 31 Aripiprazole - 13 Molindone - 1 Perphenazine - 17 2. Safety population: Control - 45 Metformin - 47 Switch - 30 Aripiprazole - 12 Molindone - 1 Perphenazine - 17 3. Efficacy population : Control - 44 Metformin - 47 Switch - 30 Aripiprazole - 12 Molindone - 1 Perphenazine - 17	0.00% 0/30 See the correct numbers for the 3 populations below. We had to exclude 5 participants (CONTROL = 2, METFORMIN = 2, SWITCH = 1). 1. Randomized population: Control - 47 Metformin - 49 Switch - 31 Aripiprazole - 13 Molindone - 1 Perphenazine - 17 2. Safety population: Control - 45 Metformin - 47 Switch - 30 Aripiprazole - 12 Molindone - 1 Perphenazine - 17 3. Efficacy population : Control - 44 Metformin - 47 Switch - 30 Aripiprazole - 12 Molindone - 1 Perphenazine - 17	2.1% 1/47 • Number of events 1 See the correct numbers for the 3 populations below. We had to exclude 5 participants (CONTROL = 2, METFORMIN = 2, SWITCH = 1). 1. Randomized population: Control - 47 Metformin - 49 Switch - 31 Aripiprazole - 13 Molindone - 1 Perphenazine - 17 2. Safety population: Control - 45 Metformin - 47 Switch - 30 Aripiprazole - 12 Molindone - 1 Perphenazine - 17 3. Efficacy population : Control - 44 Metformin - 47 Switch - 30 Aripiprazole - 12 Molindone - 1 Perphenazine - 17
Psychiatric disorders Hospitalization	0.00% 0/45 See the correct numbers for the 3 populations below. We had to exclude 5 participants (CONTROL = 2, METFORMIN = 2, SWITCH = 1). 1. Randomized population: Control - 47 Metformin - 49 Switch - 31 Aripiprazole - 13 Molindone - 1 Perphenazine - 17 2. Safety population: Control - 45 Metformin - 47 Switch - 30 Aripiprazole - 12 Molindone - 1 Perphenazine - 17 3. Efficacy population : Control - 44 Metformin - 47 Switch - 30 Aripiprazole - 12 Molindone - 1 Perphenazine - 17	3.3% 1/30 • Number of events 1 See the correct numbers for the 3 populations below. We had to exclude 5 participants (CONTROL = 2, METFORMIN = 2, SWITCH = 1). 1. Randomized population: Control - 47 Metformin - 49 Switch - 31 Aripiprazole - 13 Molindone - 1 Perphenazine - 17 2. Safety population: Control - 45 Metformin - 47 Switch - 30 Aripiprazole - 12 Molindone - 1 Perphenazine - 17 3. Efficacy population : Control - 44 Metformin - 47 Switch - 30 Aripiprazole - 12 Molindone - 1 Perphenazine - 17	2.1% 1/47 • Number of events 1 See the correct numbers for the 3 populations below. We had to exclude 5 participants (CONTROL = 2, METFORMIN = 2, SWITCH = 1). 1. Randomized population: Control - 47 Metformin - 49 Switch - 31 Aripiprazole - 13 Molindone - 1 Perphenazine - 17 2. Safety population: Control - 45 Metformin - 47 Switch - 30 Aripiprazole - 12 Molindone - 1 Perphenazine - 17 3. Efficacy population : Control - 44 Metformin - 47 Switch - 30 Aripiprazole - 12 Molindone - 1 Perphenazine - 17

Other adverse events

Additional Information

Dr. Mark Riddle

Johns Hopkins University

Phone: 410-302-6120

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place