Clinical Trial Results:
EMPHAS
Evaluation of Methylphenidate (MPH) in adults with ADHD and SUD - clinical pharmacology study
A Cross-sectional, Open-label, Non-randomized Single-Center Study on Adults with ADHD and Substance Use Disorder (SUD) Treated with Methylphenidate in Routine Clinical Practice.
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Summary
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EudraCT number |
2013-002720-16 |
Trial protocol |
SE |
Global end of trial date |
21 Jan 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
25 Jun 2022
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First version publication date |
25 Jun 2022
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
CPPM2013
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
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Sponsors
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Sponsor organisation name |
Stockholms Läns Sjukvårdsområde (SLSO)
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Sponsor organisation address |
Box 179 14, Stockholm, Sweden, 11895
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Public contact |
Clinical Trials Information, Stockholms Läns Landsting, Beroendecentrum Stockholm, 46 08123 400 00, infoberoendecentrum@sll.se
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Scientific contact |
Clinical Trials Information, Stockholms Läns Landsting, Beroendecentrum Stockholm, 46 08123 400 00, infoberoendecentrum@sll.se
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
01 Nov 2021
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
21 Jan 2020
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Global end of trial reached? |
Yes
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Global end of trial date |
21 Jan 2020
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To characterize the inter- and intraindividual variability of plasma concentrations of MPH, its enantiomers and metabolites in adults with ADHD and comorbid SUD.
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Protection of trial subjects |
The study was conducted in accordance with the Basic & Clinical Pharmacology & Toxicology policy for experimental and clinical studies, the Declaration of Helsinki, and the International Conference on Harmonization guidelines for Good Clinical Practice. Informed consent was obtained from all study subjects before inclusion. Safety were evaluated throughout the study by monitoring of adverse events (AEs), by rating symptom scale, performing laboratory tests, measurement of vital signs.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
03 Nov 2014
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Sweden: 28
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Worldwide total number of subjects |
28
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EEA total number of subjects |
28
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
28
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
First patient in: 27-MAY-2015; last patient out: 8-SEP-2017 recruitment at out-patient clinics at the Stockholm Centre for Dependency Disorders, Sweden. | |||||||||
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Pre-assignment
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Screening details |
Outpatients with clinically defined ADHD according to the DSM-IV or DSM-5 were recruited. Based primarily on logistic reasons such as the number of patients per unit, four out-patient units were chosen as study sites. The recruitment of patients was consecutive and independent of the dose of MPH prescribed. | |||||||||
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Period 1
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Period 1 title |
Methylphenidate (overall period)
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Is this the baseline period? |
Yes | |||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Not blinded | |||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Cross-sectional study Methylphenidate Men | |||||||||
Arm description |
The recruitment of patients was consecutive and independent of the dose of MPH prescribed. Subjects were eligible if they were between 18 and 64 years of age, diagnosed with ADHD according to DSM-IV or DSM-5, had at least one non-nicotine substance use disorder according to the DSM-IV or DSM-5, and treated with MPH with a minimum duration of 14 days. Twenty-eight patients with ADHD and SUD were included between 2015 and 2017. The patients could participate in the study either on a single day (assessment of inter-individual variability) or up to four separate days with 1 – 2 weeks intervals (assessment of intra-individual variability). The patients continued treatment as usual during and after study visits. | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Methylphenidate
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Investigational medicinal product code |
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Other name |
Concerta, Ritalin, Medikinet
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Pharmaceutical forms |
Capsule, hard + tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Eleven subjects were prescribed daily doses higher than 180 mg, with a median dose of 324 mg (range 198˗¬¬600 mg). Sixteen patients were prescribed extended-release MPH (Ritalin® or Medikinet®), eight patients osmotic-release oral system (OROS)-MPH (Concerta®), two patients an immediate-release formulation of MPH (Medikinet®), and two patients a combination of Ritalin® and Concerta®. Thirteen subjects were prescribed three or more MPH doses per day and only two patients received MPH once a day in the morning. There were no changes in the dosing or formulations of MPH during the participation in the study.
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Arm title
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Cross-sectional study Methylphenidate Women | |||||||||
Arm description |
The recruitment of patients was consecutive and independent of the dose of MPH prescribed. Subjects were eligible if they were between 18 and 64 years of age, diagnosed with ADHD according to DSM-IV or DSM-5, had at least one non-nicotine substance use disorder according to the DSM-IV or DSM-5, and treated with MPH with a minimum duration of 14 days. Twenty-eight patients with ADHD and SUD were included between 2015 and 2017. The patients could participate in the study either on a single day (assessment of inter-individual variability) or up to four separate days with 1 – 2 weeks intervals (assessment of intra-individual variability). The patients continued treatment as usual during and after study visits. | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Methylphenidate
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Investigational medicinal product code |
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Other name |
Concerta, Ritalin, Medikineto
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Pharmaceutical forms |
Capsule, hard + tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Eleven subjects were prescribed daily doses higher than 180 mg, with a median dose of 324 mg (range 198˗¬¬600 mg). Sixteen patients were prescribed extended-release MPH (Ritalin® or Medikinet®), eight patients osmotic-release oral system (OROS)-MPH (Concerta®), two patients an immediate-release formulation of MPH (Medikinet®), and two patients a combination of Ritalin® and Concerta®. Thirteen subjects were prescribed three or more MPH doses per day and only two patients received MPH once a day in the morning. There were no changes in the dosing or formulations of MPH during the participation in the study.
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Baseline characteristics reporting groups
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Reporting group title |
Methylphenidate
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Reporting group description |
The subjects were instructed not to take their MPH morning dose on the study visits. Instead, they received their prescribed MPH morning dose under supervision at the study unit. Venous blood samples were drawn before MPH intake and approximately five hours post-dose for drug concentration analysis. The exact times of drug intake and blood sampling were recorded. The subjects were free to leave the unit between the two sampling times. Venous blood was collected into 3 mL tubes containing an FC mixture. The samples were centrifuged within 30 minutes, after which plasma was transferred into polypropylene tubes and frozen within 15 minutes at -20°C. The frozen samples were then transported to the laboratory and analyzed with a validated enantioselective LC-MS/MS at the Department of Clinical Pharmacology, Karolinska University Hospital. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
MPH plasma concentrations
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Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The subjects were instructed not to take their MPH morning dose on the study visits. Instead, they received their prescribed MPH morning dose under supervision at the study unit. Venous blood samples were drawn before MPH intake and approximately five hours post-dose for drug concentration analysis. The exact times of drug intake and blood sampling were recorded. The subjects were free to leave the unit between the two sampling times. Venous blood was collected into 3 mL tubes containing an FC mixture. The samples were centrifuged within 30 minutes, after which plasma was transferred into polypropylene tubes and frozen within 15 minutes at -20°C. The frozen samples were then transported to the laboratory and analyzed with a validated enantioselective LC-MS/MS at the Department of Clinical Pharmacology, Karolinska University Hospital.
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Subject analysis set title |
RA plasma concentrations
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Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The subjects were instructed not to take their MPH morning dose on the study visits. Instead, they received their prescribed MPH morning dose under supervision at the study unit. Venous blood samples were drawn before MPH intake and approximately five hours post-dose for drug concentration analysis. The exact times of drug intake and blood sampling were recorded. The subjects were free to leave the unit between the two sampling times. Venous blood was collected into 3 mL tubes containing an FC mixture. The samples were centrifuged within 30 minutes, after which plasma was transferred into polypropylene tubes and frozen within 15 minutes at -20°C. The frozen samples were then transported to the laboratory and analyzed with a validated enantioselective LC-MS/MS at the Department of Clinical Pharmacology, Karolinska University Hospital.
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End points reporting groups
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Reporting group title |
Cross-sectional study Methylphenidate Men
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Reporting group description |
The recruitment of patients was consecutive and independent of the dose of MPH prescribed. Subjects were eligible if they were between 18 and 64 years of age, diagnosed with ADHD according to DSM-IV or DSM-5, had at least one non-nicotine substance use disorder according to the DSM-IV or DSM-5, and treated with MPH with a minimum duration of 14 days. Twenty-eight patients with ADHD and SUD were included between 2015 and 2017. The patients could participate in the study either on a single day (assessment of inter-individual variability) or up to four separate days with 1 – 2 weeks intervals (assessment of intra-individual variability). The patients continued treatment as usual during and after study visits. | ||
Reporting group title |
Cross-sectional study Methylphenidate Women
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Reporting group description |
The recruitment of patients was consecutive and independent of the dose of MPH prescribed. Subjects were eligible if they were between 18 and 64 years of age, diagnosed with ADHD according to DSM-IV or DSM-5, had at least one non-nicotine substance use disorder according to the DSM-IV or DSM-5, and treated with MPH with a minimum duration of 14 days. Twenty-eight patients with ADHD and SUD were included between 2015 and 2017. The patients could participate in the study either on a single day (assessment of inter-individual variability) or up to four separate days with 1 – 2 weeks intervals (assessment of intra-individual variability). The patients continued treatment as usual during and after study visits. | ||
Subject analysis set title |
MPH plasma concentrations
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
The subjects were instructed not to take their MPH morning dose on the study visits. Instead, they received their prescribed MPH morning dose under supervision at the study unit. Venous blood samples were drawn before MPH intake and approximately five hours post-dose for drug concentration analysis. The exact times of drug intake and blood sampling were recorded. The subjects were free to leave the unit between the two sampling times. Venous blood was collected into 3 mL tubes containing an FC mixture. The samples were centrifuged within 30 minutes, after which plasma was transferred into polypropylene tubes and frozen within 15 minutes at -20°C. The frozen samples were then transported to the laboratory and analyzed with a validated enantioselective LC-MS/MS at the Department of Clinical Pharmacology, Karolinska University Hospital.
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Subject analysis set title |
RA plasma concentrations
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
The subjects were instructed not to take their MPH morning dose on the study visits. Instead, they received their prescribed MPH morning dose under supervision at the study unit. Venous blood samples were drawn before MPH intake and approximately five hours post-dose for drug concentration analysis. The exact times of drug intake and blood sampling were recorded. The subjects were free to leave the unit between the two sampling times. Venous blood was collected into 3 mL tubes containing an FC mixture. The samples were centrifuged within 30 minutes, after which plasma was transferred into polypropylene tubes and frozen within 15 minutes at -20°C. The frozen samples were then transported to the laboratory and analyzed with a validated enantioselective LC-MS/MS at the Department of Clinical Pharmacology, Karolinska University Hospital.
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End point title |
Pharmacokinetic parameter MPH and RA plasma concentration | ||||||||||||||||||||
End point description |
Methylphenidate (MPH) and ritalinic acid (RA) plasma concentrations were analyzed with an enantioselective LC-MS/MS method.
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End point type |
Primary
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End point timeframe |
Venous blood samples were drawn before MPH intake and approximately five hours post-dose for drug concentration analysis.
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Statistical analysis title |
Plasma concentrations of MPH and RA | ||||||||||||||||||||
Statistical analysis description |
The subjects were instructed not to take their MPH morning dose on the study visits. Instead, they received their prescribed MPH morning dose under supervision at the study unit. Venous blood samples were drawn before MPH intake and approximately five hours post-dose for drug concentration analysis. The exact times of drug intake and blood sampling were recorded. The subjects were free to leave the unit between the two sampling times. Venous blood was collected into 3 mL tubes containing an FC m
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Comparison groups |
Cross-sectional study Methylphenidate Men v Cross-sectional study Methylphenidate Women
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Number of subjects included in analysis |
28
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||||||||||
Method |
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Parameter type |
Pharmacokinetic parameters - plasma conc | ||||||||||||||||||||
Point estimate |
79
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Confidence interval |
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level |
95% | ||||||||||||||||||||
sides |
1-sided
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lower limit |
- | ||||||||||||||||||||
upper limit |
79 | ||||||||||||||||||||
Variability estimate |
Standard deviation
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Adverse events information
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Timeframe for reporting adverse events |
From the start time of the first administration of the IMP until the final visit.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
SNOMED CT | ||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
2014
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Reporting groups
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Reporting group title |
Methylphenidate
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Reporting group description |
About 200 patients treated with MPH from all out-patient units were listed and, based primarily on logistic reasons such as the number of patients per unit, four out-patient units were chosen as study sites. The recruitment of patients was consecutive and independent of the dose of MPH prescribed. Subjects were eligible if they were between 18 and 64 years of age, diagnosed with ADHD according to DSM-IV or DSM-5, had at least one non-nicotine substance use disorder, and treated with MPH with a minimum duration of 14 days. Patients who declined to participate continued with their usual care at the clinic. The patients could participate in the study either on a single day (assessment of inter-individual variability) or up to four separate days with 1 – 2 weeks intervals (assessment of intra-individual variability). The patients continued treatment as usual during and after study visits. | ||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 3% | |||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| The study sample was small. Different pharmaceutical formulations of MPH were used, in some cases concomitantly. The study was performed in out-patients, and variable adherence to the prescribed dosing regimen may have influenced the results. | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/35040257 |
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