Examining Tolerance to CNS Stimulants in ADHD

• Sponsor: Florida International University (Other)
• Overall Status: Completed
• CT.gov ID: NCT02039908
• Collaborator: (none)
• Enrollment: 267
• Location: 1
• Arms: 2
• Duration (Months): 83
• Patients Per Site Per Month: 3.2

Study Details

Study Description

Brief Summary

Although stimulant medication is a well-established treatment for ADHD, it is often necessary for doctors to increase the dose over time to maintain the benefits of the medication. While medication can be very effective for improving symptoms of ADHD during the first year of use, it has not been found to significantly improve the long term course of children with ADHD. For example, in large research studies, groups of children who take medication for ten years do not have consistently better academic grades than groups of children who never used medication (individual results will vary from child to child).

In order to help children with ADHD achieve the best possible outcomes, it is important for doctors to study why this happens. One possible reason is development of tolerance to the medication. Tolerance means that a drug's effects decrease when it is taken consistently over time, so that an increased dose is needed to continue showing effects. Some doctors believe that children who take stimulant medication for ADHD develop tolerance to it which would explain why benefits may not persist over time, but no research studies have been done to measure whether this occurs. This study aims to see if children show a tolerance effect to stimulant medication and whether that tolerance can be prevented by taking short breaks from the medication called medication holidays.

Condition or Disease	Intervention/Treatment	Phase
Attention-deficit/Hyperactivity Disorder	Drug: Methylphenidate	Phase 4

Detailed Description

This is an innovative evaluation of tolerance using an objective measure in an analog classroom. Each subject will complete the a 10-minute math test twice a day for three weeks on optimal dose or placebo, and then be crossed over to the other condition. Within-subject drug/placebo differences will be compared over the three weeks of exposure to assess tolerance in the analog setting.

When school commences, 50% of the sample will be randomized to 7-day-a-week (continuous) dosing and 50% to 5-day-a- week (weekend holidays) dosing to examine the efficacy of prescribed weekend drug holidays for combatting need for dose escalations (tolerance) during the school year.

Participants will be assessed monthly to detect deteriorating functioning. Using a standardized protocol, study physicians will increase dose for subjects in either arm who meet defined impairment thresholds. The difference between the two dosing conditions will inform regarding how best to deal with tolerance in clinical application.

Study Design

• Study Type: Interventional
• Actual Enrollment: 267 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Examining Tolerance to CNS Stimulants in ADHD
• Study Start Date: Apr 1, 2013
• Actual Primary Completion Date: May 1, 2018
• Actual Study Completion Date: Mar 1, 2020

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Methylphenidate 7-day dosing During the school year, children in this arm will receive 7-day dosing of medication.	Drug: 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.; Other Names: Concerta
Active Comparator: Methylphenidate 5-day dosing During the school year phase, these children will receive 5-day dosing with weekend holidays.	Drug: 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.; Other Names: Concerta

Outcome Measures

Primary Outcome Measures

1. Number of Dose Changes Required Per Protocol [10 months]

   Monthly evaluations of medication efficacy will be used to determine whether dose adjustments are needed due to anticipated tolerance effects.

Secondary Outcome Measures

1. Time to First Dose Increase [10 months]

   The amount of time elapsed before a child requires a dose increase during the school year will be measured in months.

2. Endpoint Medication Dose [End of Phase 2 School Year]

   Dose of medication reported in mg/kg/day

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Years to 12 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Diagnosis of attention-deficit/hyperactivity disorder

• Full Scale IQ above 80

Exclusion Criteria:

• Psychotropic medications for conditions other than ADHD

• Active medical or psychiatric conditions that could be worsened by stimulants

• Diagnosis of Autism or Asperger's Disorder

• Documented intolerance fo methylphenidate or failed trial of OROS MPH

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Florida International University Center for Children and Families	Miami	Florida	United States	33199

Sponsors and Collaborators

• Florida International University

Investigators

• Principal Investigator: William E Pelham, Ph.D., Florida International University
• Principal Investigator: James M Swanson, Ph.D., Florida International University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jan 22, 2013

More Information

Additional Information:

• Center for Children and Families General Information

Publications

None provided.

• Responsible Party: Florida International University
• ClinicalTrials.gov Identifier: NCT02039908
• Other Study ID Numbers: MH099030
• First Posted: Jan 20, 2014
• Last Update Posted: Jun 9, 2020
• Last Verified: May 1, 2020

• Keywords provided by Florida International University: Tolerance to stimulant medication
• Additional relevant MeSH terms: Attention Deficit Disorder with Hyperactivity; Methylphenidate

Study Results

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 Detail	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
Period Title: Phase 1-Summer
STARTED	0	0	121	124
COMPLETED	0	0	109	116
NOT COMPLETED	0	0	12	8

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 Participants	267
Age (Count of Participants)
<=18 years	267 100%
Between 18 and 65 years	0 0%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	54 20.2%
Male	213 79.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	224 83.9%
Not Hispanic or Latino	43 16.1%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	2 0.7%
Native Hawaiian or Other Pacific Islander	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%
Region of Enrollment (participants) [Number]
United States	267 100%

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.
Measure Participants	124	121
Mean (Standard Deviation) [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.
Measure Participants	124	121
Mean (Standard Deviation) [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.
Measure Participants	116	109
Mean (Standard Deviation) [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 (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/129 (0%)		0/138 (0%)		0/121 (0%)		0/124 (0%)
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 (0.8%)		0/138 (0%)		1/121 (0.8%)		1/124 (0.8%)
Psychiatric disorders
Hospitalized	1/129 (0.8%)	1	0/138 (0%)	0	1/121 (0.8%)	1	1/124 (0.8%)	1
Other (Not Including 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	72/129 (55.8%)		78/138 (56.5%)		91/121 (75.2%)		85/124 (68.5%)
Gastrointestinal disorders
Appetite Loss	66/129 (51.2%)	252	72/138 (52.2%)	265	46/121 (38%)	131	51/124 (41.1%)	143
Stomachache	23/129 (17.8%)	51	24/138 (17.4%)	55	21/121 (17.4%)	29	17/124 (13.7%)	25
General disorders
Insomnia	52/129 (40.3%)	163	56/138 (40.6%)	190	46/121 (38%)	118	34/124 (27.4%)	80
Motor Tics	17/129 (13.2%)	23	19/138 (13.8%)	25	17/121 (14%)	24	14/124 (11.3%)	19
Buccal-lingual movements	15/129 (11.6%)	27	17/138 (12.3%)	29	10/121 (8.3%)	11	16/124 (12.9%)	20
Picking at skin, nailbiting	37/129 (28.7%)	83	28/138 (20.3%)	90	38/121 (31.4%)	73	37/124 (29.8%)	91
Worried/Anxious	27/129 (20.9%)	61	30/138 (21.7%)	66	25/121 (20.7%)	40	34/124 (27.4%)	63
Dull, tired, listless	27/129 (20.9%)	56	30/138 (21.7%)	61	14/121 (11.6%)	18	19/124 (15.3%)	32
Headache	17/129 (13.2%)	32	19/138 (13.8%)	32	15/121 (12.4%)	24	14/124 (11.3%)	23
Irritability	42/129 (32.6%)	97	46/138 (33.3%)	104	38/121 (31.4%)	71	36/124 (29%)	62
Tearful, depressed	25/129 (19.4%)	49	27/138 (19.6%)	53	14/121 (11.6%)	15	20/124 (16.1%)	31
Social Withdrawal	13/129 (10.1%)	13	14/138 (10.1%)	28	5/121 (4.1%)	6	10/124 (8.1%)	16

Limitations/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.