Withdrawal Study of Memantine in Pediatric Patients With Autism, Asperger's Disorder, or Pervasive Developmental Disorder Not Otherwise Specified Previously Treated With Memantine

Phase 2

Completed

Conditions: Autism
Asperger's Disorder
Pervasive Developmental Disorder - Not Otherwise Specified (PDD-NOS)
Autistic Disorder
Asperger Syndrome
Autism Spectrum Disorders

Interventions: Drug: Memantine Hydrochloride (HCl)
Drug: Placebo capsules

Registration Number: NCT01592747

Lead Sponsor: Forest Laboratories

Brief Summary: The purpose of this randomized withdrawal study is to evaluate the safety, tolerability, and efficacy of memantine compared with placebo in pediatric patients with autism, Asperger's Disorder, or Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS).

Detailed Description: This clinical study was a 12-week, multicenter, double-blind, placebo-controlled, randomized withdrawal study in pediatric outpatients with autism, Asperger's Disorder, or Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS). Patients who completed at least 12 weeks of study drug exposure and met protocol specified responder criterion in lead in Study MEM-MD-91 (NCT01592786) at two consecutive visits separated by at least two weeks were eligible to transition to this study. The responder criterion was defined as having at least a 10 point improvement (reduction in score) in the Social Responsiveness Scale (SRS) total raw score relative to the Visit 1 total raw score in Study MEM-MD-91.

Weight based dose limits were selected in this study to ensure that exposure in terms of area under the curve (AUC) was less than the predefined limit of 2100 ng·h/mL which represents a 10-fold lower exposure than observed at the NOAEL(No observed adverse effect level) of 15 mg/kg/day in juvenile rats.

The weight-based dose limits in this study were as follows:

* Group A: ≥ 60 kg; maximum 15 mg/day

* Group B: 40-59 kg; maximum 9 mg/day

* Group C: 20-39 kg; maximum 6 mg/day

* Group D: \< 20 kg; maximum 3 mg/day

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 479

Inclusion Criteria

Completed at least 12 weeks of exposure to study drug in lead-in study MEM-MD-91 (NCT01592786)
Met responder criterion at two consecutive visits separated by at least two weeks in lead-in study MEM-MD-91
Provide written informed assent, when developmentally appropriate, to participate in the study before conduct of any study-specific procedures. The parent/guardian/LAR must provide written informed consent before the patient's participation in the study. A separate written informed consent for the caregiver must also be obtained before the conduct of any study specific procedures
Have a knowledgeable caregiver who is capable of providing reliable information about the patient's condition, attending all clinic visits with the patient, and overseeing the administration of study drug. Every effort should be made to maintain the same caregiver as used in the lead-in study throughout this study
Have normal results from the physical examination, laboratory tests, ECG, and vital signs at Visit 1 of this study (last visit of Study MEM-MD-91). Any abnormal findings must be deemed not clinically significant by the Investigator and documented
Be able to speak and understand English sufficiently (or their native language if this can be accommodated by the site), as well as have a caregiver and parent/guardian/LAR who is able to speak and understand English sufficiently (or their native language if this can be accommodated by the site), to comprehend the nature of the study and to allow for the completion of all study assessments
Have a family that is sufficiently organized and stable to guarantee adequate safety monitoring and continuous attendance to clinic visits for the duration of the study
Females who are 9 years and older or who have had onset of menses must have a negative urine pregnancy test at Visit 1
Age of 6 years to 12 years at the time of entry into lead in study MEM-MD-91

Exclusion Criteria

Patients with a concurrent medical condition that might interfere with the conduct of the study, confound interpretation of the study results, or endanger the patient's well being
Significant risk of suicidality based on the Investigator's judgment, the Aberrant Behavior Checklist-Irritability subscale (ABC-I), or if appropriate, as indicated by a response of "yes" to questions 4 or 5 in the suicidal ideation section of the Children's C-SSRS (Columbia-Suicide Severity Rating Scale) or any suicidal behavior.
Patients with evidence or history of malignancy (other than excised basal cell carcinoma) or any significant hematologic, endocrine, cardiovascular (including any rhythm disorder), neurologic, respiratory, renal, hepatic, or gastrointestinal disease
Female patients of child-bearing potential who are not using or not willing to use a conventional method of contraception approved by the PI. Abstinence is an acceptable method of contraception
Patients requiring treatment with prohibited concomitant medications
Patients who, in the opinion of the Investigator, might not be suitable for the study
Employee or immediate relative of an employee of Forest Laboratories, Inc., any of its affiliates or partners, or the study center

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Memantine 1	Memantine Hydrochloride (HCl)	Patients randomized to the full dose arm will continue taking memantine at the same tolerability and weight-based dose achieved in lead-in Study MEM-MD-91. Dosing will be once daily for up to 12 weeks.
Memantine 2	Memantine Hydrochloride (HCl)	Patients randomized to the reduced dose arm will take memantine at the tolerability and weight based dose that they received in lead in Study MEM-MD-91 reduced by at least 50%. Dosing will be once daily for up to 12 weeks.
Placebo	Placebo capsules	Dosing will be once daily for up to 12 weeks.

Primary Outcome Measures

Name	Time	Method
Proportion of Patients Meeting the Criterion for Loss of Therapeutic Response (LTR) by the End of the Study (Based on Observed Cases)	Baseline (Visit 1) to week 12	Loss of Therapeutic response is defined as a worsening (increase) of at least 10 points in Social Responsiveness Scale (SRS) total raw score relative to the Visit 1 (randomization) score. The Social Responsiveness Scale (SRS) is a 65-item informant-rated assessment with total raw score ranging from 0 (no impairment) to 195 (severe social impairment). Each item is associated with 1 of 5 subscales (social awareness, social cognition, social communication, social motivation and autistic mannerisms). Each item is rated on a 4-point scale from 1 (not true) to 4 (almost always true). The scores are then transposed to a scale from 0 to 3 and scores are summed within each of the 5 subscales. A higher score indicates greater severity of social impairment.

Secondary Outcome Measures

Name	Time	Method
Time to First Loss of Therapeutic (LTR) Response	Baseline to week 12	Time to the first visit when a patient shows LTR following randomization to memantine or placebo.
Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Speech Subscale at Week 12	Baseline (Visit 1) to week 12	The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties (items 1-50) and strengths (items 51-70) in communication. There are 10 sub-scales consisting of 7 items each. The Children's Communication Checklist-2 (CCC-2) Speech Subscale consists of 7 items rated from 0 (less than once a week or never) to 3 (several times \[more than twice\] a day or always), with a total raw score of 0 (mildest) to 21 (most severe).
Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Syntax Subscale at Week 12	Baseline (Visit 1) to week 12	The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties (items 1-50) and strengths (items 51-70) in communication. There are 10 sub-scales consisting of 7 items each. The Children's Communication Checklist-2 (CCC-2) Syntax Subscale consists of 7 items rated from 0 (less than once a week or never) to 3 (several times \[more than twice\] a day or always), with a total raw score of 0 (mildest) to 21 (most severe).
Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Semantics Subscale at Week 12	Baseline (Visit 1) to week 12	The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties (items 1-50) and strengths (items 51-70) in communication. There are 10 sub-scales consisting of 7 items each. The Children's Communication Checklist-2 (CCC-2) Semantics Subscale consists of 7 items rated from 0 (less than once a week or never) to 3 (several times \[more than twice\] a day or always), with a total raw score of 0 (mildest) to 21 (most severe).
Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Coherence Subscale at Week 12	Baseline (Visit 1) to week 12	The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties (items 1-50) and strengths (items 51-70) in communication. There are 10 sub-scales consisting of 7 items each. The Children's Communication Checklist-2 (CCC-2) Coherence Subscale consists of 7 items rated from 0 (less than once a week or never) to 3 (several times \[more than twice\] a day or always), with a total raw score of 0 (mildest) to 21 (most severe).
Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Initiation Subscale at Week 12	Baseline (Visit 1) to week 12	The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties (items 1-50) and strengths (items 51-70) in communication. There are 10 sub-scales consisting of 7 items each. The Children's Communication Checklist-2 (CCC-2) Initiation Subscale consists of 7 items rated from 0 (less than once a week or never) to 3 (several times \[more than twice\] a day or always), with a total raw score of 0 (mildest) to 21 (most severe).
Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Scripted Language Subscale at Week 12	Baseline (Visit 1) to week 12	The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties (items 1-50) and strengths (items 51-70) in communication. There are 10 sub-scales consisting of 7 items each. The Children's Communication Checklist-2 (CCC-2) Scripted language Subscale consists of 7 items rated from 0 (less than once a week or never) to 3 (several times \[more than twice\] a day or always), with a total raw score of 0 (mildest) to 21 (most severe).
Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Context Subscale at Week 12	Baseline (Visit 1) to week 12	The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties (items 1-50) and strengths (items 51-70) in communication. There are 10 sub-scales consisting of 7 items each. The Children's Communication Checklist-2 (CCC-2) Context Subscale consists of 7 items rated from 0 (less than once a week or never) to 3 (several times \[more than twice\] a day or always), with a total raw score of 0 (mildest) to 21 (most severe).
Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Nonverbal Communication Subscale at Week 12	Baseline (Visit 1) to week 12	The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties (items 1-50) and strengths (items 51-70) in communication. There are 10 sub-scales consisting of 7 items each. The Children's Communication Checklist-2 (CCC-2) Nonverbal communication Subscale consists of 7 items rated from 0 (less than once a week or never) to 3 (several times \[more than twice\] a day or always), with a total raw score of 0 (mildest) to 21 (most severe).
Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Social Relations Subscale at Week 12	Baseline (Visit 1) to week 12	The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties (items 1-50) and strengths (items 51-70) in communication. There are 10 sub-scales consisting of 7 items each. The Children's Communication Checklist-2 (CCC-2) Social Relations Subscale consists of 7 items rated from 0 (less than once a week or never) to 3 (several times \[more than twice\] a day or always), with a total raw score of 0 (mildest) to 21 (most severe).
Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Interests Subscale at Week 12	Baseline (Visit 1) to week 12	The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties (items 1-50) and strengths (items 51-70) in communication. There are 10 sub-scales consisting of 7 items each. The Children's Communication Checklist-2 (CCC-2) Interests Subscale consists of 7 items rated from 0 (less than once a week or never) to 3 (several times \[more than twice\] a day or always), with a total raw score of 0 (mildest) to 21 (most severe).

Trial Locations

Locations (94): Forest Investigative Site 055
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Tucson, Arizona, United States
Forest Investigative Site 077
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Little Rock, Arkansas, United States
Forest Investigative Site 052
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Washington, District of Columbia, United States
Forest Investigative Site 065
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Maitland, Florida, United States
Forest Investigative Site 117
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Jacksonville, Florida, United States
Forest Investigative Site 085
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Oakland Park, Florida, United States
Forest Investigative Site 086
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Rockville, Maryland, United States
Forest Investigative Site 059
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Newton, Massachusetts, United States
Forest Investigative Site 108
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Springfield, Massachusetts, United States
Forest Investigative Site 090
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Memphis, Tennessee, United States
Forest Investigative Site 577
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Warszawa, Poland
Forest Investigative Site 626
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Belgrade, Serbia
Forest Investigative Site 629
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Nis, Serbia
Forest Investigative Site 628
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Novi Sad, Serbia
Forest Investigative Site 802
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Kherson,Vil. Stepanivka, Ukraine
Forest Investigative Site 075
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Bradenton, Florida, United States
Forest Investigative Site 676
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Cape Town, Western Cape, South Africa
Forest Investigative Site 051
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Houston, Texas, United States
Forest Investigative Site 092
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Tulsa, Oklahoma, United States
Forest Investigative Site 102
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Libertyville, Illinois, United States
Forest Investigative Site 132
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Johnstown, Pennsylvania, United States
Forest Investigative Site 131
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McMurray, Pennsylvania, United States
Forest Investigative Site 068
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Dothan, Alabama, United States
Forest Investigative Site 054
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Glendale, California, United States
Forest Investigative Site 109
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Imperial, California, United States
Forest Investigative Site 026
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Santa Ana, California, United States
Forest Investigative Site 096
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Los Angeles, California, United States
Forest Investigative Site 002
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Stanford, California, United States
Forest Investigative Site 078
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Boulder, Colorado, United States
Forest Investigative Site 115
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Orange City, Florida, United States
Forest Investigative Site 101
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Wellington, Florida, United States
Forest Investigative Site 023
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Naperville, Illinois, United States
Forest Investigative Site 082
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Evansville, Indiana, United States
Forest Investigative Site 095
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Lake Charles, Louisiana, United States
Forest Investigative Site 100
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Media, Pennsylvania, United States
Forest Investigative Site 376
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Budapest, Hungary
Forest Investigative Site 526
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Wellington, New Zealand
Forest Investigative Site 106
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Wichita, Kansas, United States
Forest Investigative Site 073
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Centennial, Colorado, United States
Forest Investigative Site 116
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Lincoln, Nebraska, United States
Forest Investigative Site 097
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Lincoln, Nebraska, United States
Forest Investigative Site 069
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Avon Lake, Ohio, United States
Forest Investigative Site 081
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Albuquerque, New Mexico, United States
Forest Investigative Site 127
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Toms River, New Jersey, United States
Forest Investigative Site 130
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Henderson, Nevada, United States
Forest Investigative Site 136
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Neptune, New Jersey, United States
Forest Investigative Site 053
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Gresham, Oregon, United States
Forest Investigative Site 001
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Columbus, Ohio, United States
Forest Investigative Site 119
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Charleston, West Virginia, United States
Forest Investigative Site 064
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Charlottesville, Virginia, United States
Forest Investigative Site 070
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The Woodlands, Texas, United States
Forest Investigative Site 141
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Ogden, Utah, United States
Forest Investigative Site 028
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Clinton, Utah, United States
Forest Investigative Site 204
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Brussel, Belgium
Forest Investigative Site 226
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Bogotá, Colombia
Forest Investigative Site 329
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Bron Cedex, France
Forest Investigative Site 113
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Norfolk, Virginia, United States
Forest Investigative Site 203
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Bruxelles, Belgium
Forest Investigative Site 228
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Bello, Colombia
Forest Investigative Site 276
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Tallinn, Estonia
Forest Investigative Site 071
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Bothell, Washington, United States
Forest Investigative Site 063
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Middleton, Wisconsin, United States
Forest Investigative Site 704
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Yangsan-si, Gyeongsangnam-do, Korea, Republic of
Forest Investigative Site 579
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Gdansk, Poland
Forest Investigative Site 578
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Gdansk, Poland
Forest Investigative Site 807
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Kharkiv, Ukraine
Forest Investigative Site 804
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Kyiv, Ukraine
Forest Investigative Site 703
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Seoul, Korea, Republic of
Forest Investigative Site 378
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Budapest, Hungary
Forest Investigative Site 381
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Budapest, Hungary
Forest Investigative Site 627
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Belgrade, Serbia
Forest Investigative Site 728
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Sabadell, Barcelona, Spain
Forest Investigative Site 401
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Kopavogur, Iceland
Forest Investigative Site 452
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Siena, Italy
Forest Investigative Site 576
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Kobierzyce, Poland
Forest Investigative Site 702
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Seoul, Korea, Republic of
Forest Investigative Site 453
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Roma, Italy
Forest Investigative Site 701
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Seoul, Korea, Republic of
Forest Investigative Site 107
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Albuquerque, New Mexico, United States
Forest Investigative Site 005
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Phoenix, Arizona, United States
Forest Investigative Site 118
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Miami, Florida, United States
Forest Investigative Site 029
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Salt Lake City, Utah, United States
Forest Investigative Site 021
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San Francisco, California, United States
Forest Investigative Site 125
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Orlando, Florida, United States
Forest Investigative Site 062
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Orlando, Florida, United States
Forest Investigative Site 056
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Indianapolis, Indiana, United States
Forest Investigative Site 104
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Las Vegas, Nevada, United States
Forest Investigative Site 067
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Tampa, Florida, United States
Forest Investigative Site 057
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Nashville, Tennessee, United States
Forest Investigative Site 061
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Louisville, Kentucky, United States
Forest Investigative Site 019
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Oklahoma City, Oklahoma, United States
Forest Investigative Site 080
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Gainesville, Florida, United States
Forest Investigative Site 072
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Chapel Hill, North Carolina, United States
Forest Investigative Site 105
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Charleston, South Carolina, United States