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Examining Tolerance to CNS Stimulants in ADHD

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ClinicalTrials.gov Identifier: NCT02039908
Recruitment Status : Completed
First Posted : January 20, 2014
Results First Posted : September 17, 2019
Last Update Posted : June 9, 2020
Sponsor:
Information provided by (Responsible Party):
Florida International University

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Attention-deficit/Hyperactivity Disorder
Intervention Drug: Methylphenidate
Enrollment 267
Recruitment Details Participants were recruited in 4 annual cohorts from 2013-2016. Participants could be referred by schools, physicians, or community advertisement; interested parents completed phone screens and a clinic intake to assess inclusionary and exclusionary criteria.
Pre-assignment Details Because all participants were required to be enrolled in a Summer Treatment Program, some participants withdrew after consenting because they were unable to make the time commitment to the 8-week summer program.
Arm/Group Title Phase 1-Summer; Medication First, Then Placebo Phase 1-Summer; Placebo First, Then Medication Phase 2 School Year - 7-Day Dosing Phase 2 School Year; 5-Day Dosing
Hide Arm/Group Description In the first phase of the study, children participated in a crossover design of placebo and optimal-dose methylphenidate for 13 days in each condition. After a 9-day titration period, the Medication First group received their optimal dose of methylphenidate for 13 days, a 2-day medication/placebo probe, a 2-day washout, then placebo for 13 days and a 2-day medication/placebo probe. In the first phase of the study, children participated in a crossover design of placebo and optimal-dose methylphenidate for 13 days in each condition. After a 9-day titration period, the Placebo First group received placebo for 13 days, a 2-day medication/placebo probe, a 2-day washout, then optimal-dose medication for 13 days and a 2-day medication/placebo probe. During the school year, all participants took their optimal dose determined in Phase 1 of the study for the entire school year. These partcipants received medication 7-days a week for the entire year. During the school year, all participants took their optimal dose determined during Phase 1 for the entire school year. These participants received medication on school-days only with drug holidays over weekends.
Period Title: Phase 1-Summer
Started 129 138 0 0
Completed 116 132 0 0
Not Completed 13 6 0 0
Reason Not Completed
Withdrawal by Subject             7             6             0             0
Protocol Violation             6             0             0             0
Period Title: Phase 2-School Year
Started [1] 0 0 121 124
Completed 0 0 109 116
Not Completed 0 0 12 8
Reason Not Completed
Lost to Follow-up             0             0             1             3
Protocol Violation             0             0             3             0
Withdrawal by Subject             0             0             8             5
[1]
Three participants elected not to continue in the study for the school -year phase.
Arm/Group Title Phase 1-Summer
Hide Arm/Group Description In the first phase of the study, all children participate in a crossover design of placebo and optimal-dose methylphenidate for 13 days in each condition.
Overall Number of Baseline Participants 267
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 267 participants
<=18 years
267
 100.0%
Between 18 and 65 years
0
   0.0%
>=65 years
0
   0.0%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 267 participants
Female
54
  20.2%
Male
213
  79.8%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 267 participants
Hispanic or Latino
224
  83.9%
Not Hispanic or Latino
43
  16.1%
Unknown or Not Reported
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 267 participants
American Indian or Alaska Native
0
   0.0%
Asian
2
   0.7%
Native Hawaiian or Other Pacific Islander
0
   0.0%
Black or African American
22
   8.2%
White
237
  88.8%
More than one race
6
   2.2%
Unknown or Not Reported
0
   0.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 267 participants
267
1.Primary Outcome
Title Number of Dose Changes Required Per Protocol
Hide Description Monthly evaluations of medication efficacy will be used to determine whether dose adjustments are needed due to anticipated tolerance effects.
Time Frame 10 months
Hide Outcome Measure Data
Hide Analysis Population Description
All participants who began Phase 2 were included in analysis
Arm/Group Title Methylphenidate 7-day Dosing Methylphenidate 5-day Dosing
Hide Arm/Group Description:

During the school year, children in this arm will receive 7-day dosing of medication.

Methylphenidate: Children will receive a double-blind assessment to determine their optimal starting dose of Concerta. Doses will be adjusted over the course of the school year and inceased if tolerance to the medication is detected.

During the school year phase, these children will receive 5-day dosing with weekend holidays.

Methylphenidate: Children will receive a double-blind assessment to determine their optimal starting dose of Concerta. Doses will be adjusted over the course of the school year and inceased if tolerance to the medication is detected.

Overall Number of Participants Analyzed 124 121
Mean (Standard Deviation)
Unit of Measure: Number of Increases
1.79  (1.16) 1.61  (1.08)
2.Secondary Outcome
Title Time to First Dose Increase
Hide Description The amount of time elapsed before a child requires a dose increase during the school year will be measured in months.
Time Frame 10 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Methylphenidate 7-day Dosing Methylphenidate 5-day Dosing
Hide Arm/Group Description:

During the school year, children in this arm will receive 7-day dosing of medication.

Methylphenidate: Children will receive a double-blind assessment to determine their optimal starting dose of Concerta. Doses will be adjusted over the course of the school year and inceased if tolerance to the medication is detected.

During the school year phase, these children will receive 5-day dosing with weekend holidays.

Methylphenidate: Children will receive a double-blind assessment to determine their optimal starting dose of Concerta. Doses will be adjusted over the course of the school year and inceased if tolerance to the medication is detected.

Overall Number of Participants Analyzed 124 121
Mean (Standard Deviation)
Unit of Measure: Months
3.8  (3.4) 4.1  (3.5)
3.Secondary Outcome
Title Endpoint Medication Dose
Hide Description Dose of medication reported in mg/kg/day
Time Frame End of Phase 2 School Year
Hide Outcome Measure Data
Hide Analysis Population Description
Only participants who completed the entire school year are used in endpoint medication dosing calculations.
Arm/Group Title Methylphenidate 7-day Dosing Methylphenidate 5-day Dosing
Hide Arm/Group Description:

During the school year, children in this arm will receive 7-day dosing of medication.

Methylphenidate: Children will receive a double-blind assessment to determine their optimal starting dose of Concerta. Doses will be adjusted over the course of the school year and inceased if tolerance to the medication is detected.

During the school year phase, these children will receive 5-day dosing with weekend holidays.

Methylphenidate: Children will receive a double-blind assessment to determine their optimal starting dose of Concerta. Doses will be adjusted over the course of the school year and inceased if tolerance to the medication is detected.

Overall Number of Participants Analyzed 116 109
Mean (Standard Deviation)
Unit of Measure: Mg/kg/day
1.30  (0.43) 1.24  (0.41)
Time Frame During Phase 1, side effects ratings were collected from parents daily for the first 2 weeks of the summer and weekly for the final 6 weeks of the summer. During Phase 2, side-effects ratings were completed by parents monthly at medication dispensing visits.
Adverse Event Reporting Description Parents completed the Pittsburgh Side Effects Rating Scale, rating each of the most common side effects of stimulant medication on a scale of None, Mild, Moderate, or Severe. Adverse events were counted if parents rated the side effect at the Moderate or Severe level on at least one occasion,
 
Arm/Group Title Phase 1-Medication First Phase 1 - Placebo First Phase 2 - 7-Day Dosing Phase 2 - 5-Day Dosing
Hide Arm/Group Description In the first phase of the study, children participated in a crossover design of placebo and optimal-dose methylphenidate for 13 days in each condition. After a 9-day titration period, the Medication First group received methylphenidate for 13 days, a 2-day medication/placebo probe, a 2-day washout, then placebo for 13 days and a 2-day medication/placebo probe. In the first phase of the study, children participated in a crossover design of placebo and optimal-dose methylphenidate for 13 days in each condition. After a 9-day titration period, the Placebo First group received placebo for 13 days, a 2-day medication/placebo probe, a 2-day washout, then optimal-dose medication for 13 days and a 2-day medication/placebo probe. During the school year, all participants took their optimal dose determined in Phase 1 of the study for the entire school year. These participants received medication 7-days a week for the entire year During the school year, all participants took their optimal dose determined during Phase 1 for the entire school year. These participants received medication on school-days only with drug holidays over weekends.
All-Cause Mortality
Phase 1-Medication First Phase 1 - Placebo First Phase 2 - 7-Day Dosing Phase 2 - 5-Day Dosing
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/129 (0.00%)      0/138 (0.00%)      0/121 (0.00%)      0/124 (0.00%)    
Hide Serious Adverse Events
Phase 1-Medication First Phase 1 - Placebo First Phase 2 - 7-Day Dosing Phase 2 - 5-Day Dosing
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   1/129 (0.78%)      0/138 (0.00%)      1/121 (0.83%)      1/124 (0.81%)    
Psychiatric disorders         
Hospitalized * [1]  1/129 (0.78%)  1 0/138 (0.00%)  0 1/121 (0.83%)  1 1/124 (0.81%)  1
*
Indicates events were collected by non-systematic assessment
[1]
Referred by parent for inpatient psychiatric treatment due to comorbid mental health issues.
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Phase 1-Medication First Phase 1 - Placebo First Phase 2 - 7-Day Dosing Phase 2 - 5-Day Dosing
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   72/129 (55.81%)      78/138 (56.52%)      91/121 (75.21%)      85/124 (68.55%)    
Gastrointestinal disorders         
Appetite Loss  [1]  66/129 (51.16%)  252 72/138 (52.17%)  265 46/121 (38.02%)  131 51/124 (41.13%)  143
Stomachache  [2]  23/129 (17.83%)  51 24/138 (17.39%)  55 21/121 (17.36%)  29 17/124 (13.71%)  25
General disorders         
Insomnia   52/129 (40.31%)  163 56/138 (40.58%)  190 46/121 (38.02%)  118 34/124 (27.42%)  80
Motor Tics  [3]  17/129 (13.18%)  23 19/138 (13.77%)  25 17/121 (14.05%)  24 14/124 (11.29%)  19
Buccal-lingual movements  [4]  15/129 (11.63%)  27 17/138 (12.32%)  29 10/121 (8.26%)  11 16/124 (12.90%)  20
Picking at skin, nailbiting  [5]  37/129 (28.68%)  83 28/138 (20.29%)  90 38/121 (31.40%)  73 37/124 (29.84%)  91
Worried/Anxious  [6]  27/129 (20.93%)  61 30/138 (21.74%)  66 25/121 (20.66%)  40 34/124 (27.42%)  63
Dull, tired, listless  [7]  27/129 (20.93%)  56 30/138 (21.74%)  61 14/121 (11.57%)  18 19/124 (15.32%)  32
Headache  [8]  17/129 (13.18%)  32 19/138 (13.77%)  32 15/121 (12.40%)  24 14/124 (11.29%)  23
Irritability  [9]  42/129 (32.56%)  97 46/138 (33.33%)  104 38/121 (31.40%)  71 36/124 (29.03%)  62
Tearful, depressed  [10]  25/129 (19.38%)  49 27/138 (19.57%)  53 14/121 (11.57%)  15 20/124 (16.13%)  31
Social Withdrawal  [11]  13/129 (10.08%)  13 14/138 (10.14%)  28 5/121 (4.13%)  6 10/124 (8.06%)  16
Indicates events were collected by systematic assessment
[1]
Moderate or Severe Appetite Loss
[2]
Parent rating of moderate or severe stomach ache
[3]
Rating of moderate or severe motor tics
[4]
Parent rating of moderate or severe buccal-lingual movements
[5]
Parent rating of moderate or severe picking, nail-biting, etc.
[6]
Parent rating of moderate or severe worry/anxiety
[7]
Parent rating of moderate or severe dullness/tiredness/listlessness
[8]
Parent rating of moderate or severe headache
[9]
Parent rating of moderate or severe irritability
[10]
Parent rating of moderate or severe tearfulness or sadness
[11]
Parent rating of moderate or severe social withdrawal
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: William E. Pelham, Jr., Ph.D.
Organization: Florida International University
Phone: 305-348-0477
EMail: wpelham@fiu.edu
Layout table for additonal information
Responsible Party: Florida International University
ClinicalTrials.gov Identifier: NCT02039908    
Other Study ID Numbers: MH099030
First Submitted: March 7, 2013
First Posted: January 20, 2014
Results First Submitted: July 29, 2019
Results First Posted: September 17, 2019
Last Update Posted: June 9, 2020