Examining Tolerance to CNS Stimulants in ADHD

• 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: Florida International University
• 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

Participant Flow

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
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.

Baseline Characteristics

Arm/Group Title		Phase 1-Summer
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
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

Outcome Measures

1. Primary Outcome

Title	Number of Dose Changes Required Per Protocol
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

Outcome Measure Data

Analysis Population Description

All participants who began Phase 2 were included in analysis

Arm/Group Title	Methylphenidate 7-day Dosing	Methylphenidate 5-day Dosing
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
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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Methylphenidate 7-day Dosing	Methylphenidate 5-day Dosing
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
Description	Dose of medication reported in mg/kg/day
Time Frame	End of Phase 2 School Year

Outcome Measure Data

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
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)

Adverse Events

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
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%)
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.
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

Limitations and Caveats

[Not Specified]

More Information

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

• Name/Title: William E. Pelham, Jr., Ph.D.
• Organization: Florida International University
• Phone: 305-348-0477
• EMail: wpelham@fiu.edu

• 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