Methylphenidate for ADHD

(AMPAIII Trial)

Recruiting at 1 trial location

Overseen By Steve W Wu, MD

Age: < 18

Sex: Any

Trial Phase: Phase 4

Sponsor: Donald Gilbert, MD, MS, FAAN, FAAP

Must not be taking: Antidepressants, Non-stimulants, Dopamine blockers, Mood stabilizers

Disqualifiers: Autism, Epilepsy, Bipolar, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 4

Duration: 4 weeks

214 Participants Needed

Trial Summary

What is the purpose of this trial?

Attention-Deficit/Hyperactivity Disorder (ADHD) is the most commonly diagnosed neurobehavioral disorder in childhood. Children with ADHD struggle in school due to problems with attention and high levels of impulsivity and hyperactivity. They are at substantially increased risk for long-term difficulties into adulthood, including academic underachievement, substance abuse, and criminal behavior. The diagnosis of ADHD, which is based on subjective ratings by parents and teachers, likely results from multiple different, overlapping differences in circuits of the brain responsible for attention and impulse control. However, we do not have any scientific or clinical tests that allow us to understand these circuits. In an effort to improve ADHD outcomes, we have used a technology called Transcranial Magnetic Stimulation (TMS) to identify highly reliable measurements of brain function. We have identified two very promising measures that are abnormal in children with ADHD and, importantly, also predict the severity of ADHD behaviors. The goal of this project is to determine if these two TMS measurements could be used to help better guide ADHD treatment. To do this, we will perform three investigations in 8 to 12 year old children to determine: 1) test-retest reliability; 2) pharmacologic responsiveness; and 3) correlations with two domains of function relevant to ADHD: "Cognitive Control" and "Emotional Valence." Through these investigations, we aim to determine whether these two TMS brain measures are reliable and meaningful enough to be used to help improve precision of individually-targeted and effective ADHD treatments.

Will I have to stop taking my current medications?

If your child is currently taking stimulant medications for ADHD, they will need to stop taking them as specified in the study procedures. However, if they are taking antidepressants, non-stimulant ADHD medications, or other listed medications, they cannot participate in the trial.

What evidence supports the effectiveness of the drug Methylphenidate for treating ADHD?

Research shows that controlled-delivery methylphenidate, like Metadate CD, is effective in reducing ADHD symptoms in children and adolescents, performing better than a placebo and similarly to immediate-release versions. Additionally, dexmethylphenidate, a form of methylphenidate, has been found effective at managing ADHD symptoms at lower doses. ^{1 2 3 4 5}

Is methylphenidate generally safe for humans?

Methylphenidate, used in various forms like Ritalin and Concerta, is generally well tolerated in treating ADHD, with most side effects being mild and resolving quickly. In France, where it is strictly regulated, 21 adverse reactions were reported, mostly non-serious, suggesting it is safe when used as prescribed. ^{1 6 7 8 9}

How does the drug Methylphenidate differ from other ADHD treatments?

Methylphenidate, especially in its controlled-delivery form, offers superior control of ADHD symptoms during the school day compared to some other formulations, making it particularly useful for children and adolescents who need symptom management throughout the day. Additionally, dexmethylphenidate, a single isomer version of methylphenidate, provides effective management at half the dose, potentially reducing side effects and drug interactions. ^{1 3 4 7 10}

Research Team

Donald L Gilbert, MD

Principal Investigator

Children's Hospital Medical Center, Cincinnati

Stewart H Mostofsky, MD

Principal Investigator

Hugo W. Moser Research Institute at Kennedy Krieger, Inc.

Eligibility Criteria

This trial is for right-handed children aged 8-12 years with ADHD, who are willing to suspend stimulant medications if prescribed. Healthy controls without ADHD or other disorders can also join. It excludes those on certain medications, with onset of menses, pregnancy, or serious neurological conditions.

Inclusion Criteria

I can understand and agree to the study's terms.

I am between 8 and 12 years old.

For children with ADHD prescribed stimulant medications, willing to suspend taking medications as specified in the study procedures

Exclusion Criteria

I have been diagnosed with a speech/language disorder or reading disability.

You have a device implanted in your body, such as a brain stimulator or pacemaker.

I am currently taking medication for depression, ADHD, or mood stabilization.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Baseline Assessment

Participants complete diagnostic and psychoeducational testing, and parents complete standardized questionnaires and a psychiatric diagnostic interview

1 day

1 visit (in-person)

Treatment

Participants undergo pre-dose TMS, receive either MPH or placebo, and then undergo post-dose TMS

4 weeks

2 visits (in-person, 2-week intervals)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Methylphenidate
• Placebo

Trial Overview The study tests the effects of Methylphenidate (a common ADHD medication) against a placebo in improving brain function measures obtained by Transcranial Magnetic Stimulation (TMS). The goal is to refine treatment precision for ADHD in children.

Participant Groups

Group I: Attention Deficit Hyperactivity Disorder (ADHD) Experimental Treatment 2 Interventions

8 to 12 year old children diagnosed with ADHD. Randomized, blinded, single dose, placebo controlled, crossover trial.

Group II: Typically developing controls (TDC) Active Control 1 Intervention

Typically developing controls - 8 to 12 year old children

Methylphenidate is already approved in United States, Canada, European Union for the following indications:

Approved in United States as Methylphenidate for:

• Attention Deficit Hyperactivity Disorder (ADHD)
• Narcolepsy

Approved in Canada as Methylphenidate for:

• Attention Deficit Hyperactivity Disorder (ADHD)
• Narcolepsy

Approved in European Union as Methylphenidate for:

• Attention Deficit Hyperactivity Disorder (ADHD)
• Narcolepsy

Who Is Running the Clinical Trial?

Donald Gilbert, MD, MS, FAAN, FAAP

Lead Sponsor

Trials

1

Recruited

210+

Hugo W. Moser Research Institute at Kennedy Krieger, Inc.

Collaborator

Trials

93

Recruited

25,200+

Findings from Research

Controlled-delivery methylphenidate (methylphenidate CD) is effective and well tolerated for treating ADHD in children aged 6 and older, showing superior control of symptoms compared to osmotic release methylphenidate during a typical school day.

In clinical trials lasting 3 weeks, methylphenidate CD was found to be more effective than a placebo and equally effective as immediate-release methylphenidate, making it a strong option for managing ADHD symptoms during school hours.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Methylphenidate controlled-delivery capsules (EquasymXL, Metadate CD): a review of its use in the treatment of children and adolescents with attention-deficit hyperactivity disorder. Anderson, VR., Keating, GM.[2018]

In a study involving children aged 6-12 years with ADHD, once-daily modified-release methylphenidate (EqXL) was found to be non-inferior to twice-daily immediate-release methylphenidate (MPH-IR) in reducing ADHD symptoms over three weeks.

Both formulations of methylphenidate were significantly more effective than placebo, and all treatments were well tolerated, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of the clinical efficacy of twice-daily Ritalin and once-daily Equasym XL with placebo in children with Attention Deficit/Hyperactivity Disorder. Findling, RL., Quinn, D., Hatch, SJ., et al.[2018]

Dexmethylphenidate, a chirally pure form of methylphenidate, has been shown to effectively manage ADHD in children at half the dose of traditional Ritalin, based on clinical trials involving 684 children.

The drug works by inhibiting the reuptake of norepinephrine and dopamine, and has been found to be well tolerated, with ongoing research to further understand its therapeutic action.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dexmethylphenidate--Novartis/Celgene. Focalin, D-MPH, D-methylphenidate hydrochloride, D-methylphenidate, dexmethylphenidate, dexmethylphenidate hydrochloride. [2018]

Controlled-delivery methylphenidate (methylphenidate CD) is effective and well-tolerated for treating ADHD in children aged 6 and older, showing superior control of symptoms compared to osmotic release methylphenidate during a typical school day.

In clinical trials lasting 3 weeks, methylphenidate CD was found to be more effective than a placebo and equally effective as immediate-release methylphenidate, making it a strong option for managing ADHD symptoms during school hours.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Spotlight on methylphenidate controlled-delivery capsules (Equasym XL, Metadate CD) in the treatment of children and adolescents with attention-deficit hyperactivity disorder. Anderson, VR., Keating, GM.[2019]

In a study involving 105 children and adolescents with ADHD, switching from immediate-release methylphenidate (MPH) to OROS MPH (a long-acting formulation) maintained and potentially improved ADHD symptom control over 21 days.

Approximately 75% of parents and investigators rated the OROS MPH therapy as good or excellent, indicating it was well tolerated and effective, particularly in managing symptoms during the after-school period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Symptom control in children and adolescents with attention-deficit/hyperactivity disorder on switching from immediate-release MPH to OROS MPH Results of a 3-week open-label study. Remschmidt, H., Hoare, P., Ettrich, C., et al.[2022]

In a study involving 308 patients aged 6-17 with ADHD, 65% showed significant improvement after 3 weeks of treatment with Metadate CD, indicating its effectiveness in real-world clinical practice.

The majority of patients (87%) reported satisfaction with Metadate CD, and those switching from other methylphenidate formulations found it to be as effective or better, with adverse events aligning with existing safety profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A postmarketing clinical experience study of Metadate CD. Dirksen, SJ., D'Imperio, JM., Birdsall, D., et al.[2019]

In a 7-week study involving 226 adults with ADHD, OROS methylphenidate significantly improved ADHD symptoms compared to placebo, as shown by lower scores on the Adult ADHD Investigator Symptom Report Scale.

The treatment was well tolerated, with no serious adverse events reported, and a higher percentage of participants on OROS methylphenidate were classified as responders compared to those on placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of OROS methylphenidate in adults with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled, double-blind, parallel group, dose-escalation study. Adler, LA., Zimmerman, B., Starr, HL., et al.[2022]

A review of the French Pharmacovigilance database revealed 21 reported adverse drug reactions related to methylphenidate, with 16 cases suspected to be linked to the medication; these were mostly mild and resolved quickly.

The findings indicate that there is no evidence of methylphenidate misuse or overuse among the 1300 to 4000 children treated in France, supporting the need for continued strict prescription regulations to prevent potential misuse.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Utilization of methylphenidate(Ritalin) in France]. Frances, C., Hoizey, G., Millart, H., et al.[2013]

In a study of 28 children aged 6-12, lisdexamfetamine dimesylate (LDX) effectively reduced ADHD symptoms, but stimulant-naïve children experienced more severe treatment-emergent adverse events (TEAEs) like trouble sleeping and stomach pain compared to those with prior stimulant exposure.

The study suggests that previous exposure to stimulant medications may influence the type and severity of side effects experienced, highlighting the need for further research with larger samples to better understand these effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse events in medication treatment-naïve children with attention-deficit/hyperactivity disorder: results from a small, controlled trial of lisdexamfetamine dimesylate. Wigal, SB., Wong, AA., Jun, A., et al.[2015]

In a study of 53 pediatric ADHD patients switched from OROS-MPH to Novo-MPH ER-C, 87% experienced destabilization of their condition, indicating that the two medications are not therapeutically equivalent despite being bioequivalent.

Patients switched to Novo-MPH ER-C reported a shorter duration of effect and different side effects compared to those who remained on OROS-MPH, suggesting that treatment disruptions can significantly impact ADHD management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The clinical impact of switching attention deficit hyperactivity disorder patients from OROS(®)-MPH to Novo-MPH ER-C(®): A paediatric practice review. van Stralen, JP.[2021]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Methylphenidate controlled-delivery capsules (EquasymXL, Metadate CD): a review of its use in the treatment of children and adolescents with attention-deficit hyperactivity disorder. [2018]

2. Germany pubmed.ncbi.nlm.nih.gov

Comparison of the clinical efficacy of twice-daily Ritalin and once-daily Equasym XL with placebo in children with Attention Deficit/Hyperactivity Disorder. [2018]

3. New Zealand pubmed.ncbi.nlm.nih.gov

Dexmethylphenidate--Novartis/Celgene. Focalin, D-MPH, D-methylphenidate hydrochloride, D-methylphenidate, dexmethylphenidate, dexmethylphenidate hydrochloride. [2018]

4. New Zealand pubmed.ncbi.nlm.nih.gov

Spotlight on methylphenidate controlled-delivery capsules (Equasym XL, Metadate CD) in the treatment of children and adolescents with attention-deficit hyperactivity disorder. [2019]

5. Germany pubmed.ncbi.nlm.nih.gov

Symptom control in children and adolescents with attention-deficit/hyperactivity disorder on switching from immediate-release MPH to OROS MPH Results of a 3-week open-label study. [2022]

6. England pubmed.ncbi.nlm.nih.gov

A postmarketing clinical experience study of Metadate CD. [2019]

7. United States pubmed.ncbi.nlm.nih.gov

Efficacy and safety of OROS methylphenidate in adults with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled, double-blind, parallel group, dose-escalation study. [2022]

8. France pubmed.ncbi.nlm.nih.gov

[Utilization of methylphenidate(Ritalin) in France]. [2013]

9. United States pubmed.ncbi.nlm.nih.gov

Adverse events in medication treatment-naïve children with attention-deficit/hyperactivity disorder: results from a small, controlled trial of lisdexamfetamine dimesylate. [2015]

10. England pubmed.ncbi.nlm.nih.gov

The clinical impact of switching attention deficit hyperactivity disorder patients from OROS(®)-MPH to Novo-MPH ER-C(®): A paediatric practice review. [2021]