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| Name | Class |
|---|---|
| Azienda Ospedaliera San Gerardo di Monza | OTHER |
| Ministry of Health, Italy | OTHER_GOV |
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There are no guidelines on the first maintenance daily dose of antiepileptic drugs (AEDs) in newly diagnosed, previously untreated epilepsy. Original trials and Cochrane reviews show that seizure remission can be achieved with differing daily doses. In clinical practice, the first maintenance dose varies significantly. In contrast, the risk of adverse treatment effects increases with dosage. There is thus the need to identify the lowest effective dose for treatment start. This background prompted us to undertake a randomized multicenter pragmatic non-inferiority trial comparing standard to low daily doses of AEDs to demonstrate that low doses are at least as effective as standard doses (as indicated by the national formulary) but are better tolerated and are associated with a better quality of life. If proven as effective as the standard dose, a low daily dose of AEDs is a benefit to the patient in terms of tolerability and safety and a source of savings for the National Health System.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Low dose | Experimental | Dosage is in mg: low dose carbamazepine, 300 ; low dose levetiracetam, 500; low dose valproate, 300; low dose zonisamide, 150; low dose oxcarbazepine, 600; low dose topiramate, 100; low dose lamotrigine, 100; low dose gabapentin, 450. Study drugs are in form of tablets for daily administration. Study drug administration duration is 12 months. The choice of the drug is left to the caring physician's discretion but it must be limited to the AEDs marketed for monotherapy use. All the study drugs will be used according to the respective SPCs, which will be sent by the promoter to all the study investigators. |
|
| Standard dose | Active Comparator | Dosage is in mg: standard dose carbamazepine 600; standard dose levetiracetam 1000; standard dose valproate, 600; standard dose zonisamide 300; standard dose oxcarbazepine 1200; standard dose topiramate, 200; standard dose lamotrigine, 200; standard dose gabapentin 900. Study drugs are in form of tablets for daily administration. Study drug administration duration is 12 months. The choice of the drug is left to the caring physician's discretion but it must be limited to the AEDs marketed for monotherapy use. All the study drugs will be used according to the respective SPCs, which will be sent by the promoter to all the study investigators. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Low dose carbamazepine | Drug | Carbamazepine, 300 mg/die |
|
|
| Measure | Description | Time Frame |
|---|---|---|
| Treatment Failure | The proportion of patients experiencing a treatment failure motivated by the need to change the assigned dose or the assigned drug for seizure relapse during the follow-up. All proportions are reported as percentages. | 12 months |
| Measure | Description | Time Frame |
|---|---|---|
| Drug-related Adverse Events | the proportion of patients experiencing a treatment failure motivated by intolerable drug-related adverse events during the follow-up; | 12 months |
| PSQ-18, Italian Version |
Not provided
Inclusion Criteria:
Exclusion Criteria:
A patient will be excluded if at least one of the following criteria will be met:
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| Name | Affiliation | Role |
|---|---|---|
| Ettore Beghi, MD | Istituto Di Ricerche Farmacologiche Mario Negri | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| ASST Monza Ospedale San Gerardo | Monza | 20900 | Italy |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 21606654 | Background | Abimbola S, Martiniuk AL, Hackett ML, Anderson CS. The influence of design and definition on the proportion of general epilepsy cohorts with remission and intractability. Neuroepidemiology. 2011;36(3):204-12. doi: 10.1159/000327497. Epub 2011 May 24. | |
| 16098770 | Background | Beghi E, Niero M, Roncolato M. Validity and reliability of the Italian version of the Quality-of-Life in Epilepsy Inventory (QOLIE-31). Seizure. 2005 Oct;14(7):452-8. doi: 10.1016/j.seizure.2005.07.008. Epub 2005 Aug 10. |
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The pre-planned sample size of 374 participants was not reached due to COVID-19 pandemic and difficulties of each center in satisfying the inclusion criteria. The total number of enrolled and randomized patients was 58.
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| ID | Title | Description |
|---|---|---|
| FG000 | Low Dose | Dosage is in mg: low dose carbamazepine, 300 ; low dose levetiracetam, 500; low dose valproate, 300; low dose zonisamide, 150; low dose oxcarbazepine, 600; low dose topiramate, 100; low dose lamotrigine, 100; low dose gabapentin, 450. Study drugs are in form of tablets for daily administration. Study drug administration duration is 12 months. The choice of the drug is left to the caring physician's discretion but it must be limited to the AEDs marketed for monotherapy use. All the study drugs will be used according to the respective SPCs, which will be sent by the promoter to all the study investigators. Low dose carbamazepine: Carbamazepine, 300 mg/die Low dose levetiracetam: Levetiracetam 500 mg/die Low dose valproate: Valproate 300 mg/die Low dose zonisamide: Zonisamide 150 mg/die Low dose oxcarbazepine: Oxcarbazepine 600 mg/die Low dose topiramate: Topiramate 100 mg/die Low dose lamotrigine: Lamotrigine 100 mg/die Low dose gabapentin: Gabapentin 450 mg/die |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Dec 20, 2021 |
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This is a multicenter randomized pragmatic parallel-group single-blind non-inferiority trial.
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| Standard dose carbamazepine | Drug | Carbamazepine 600 mg/die |
|
|
| Low dose levetiracetam | Drug | Levetiracetam 500 mg/die |
|
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| Standard dose levetiracetam | Drug | Levetiracetam 1000 mg/die |
|
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| Low dose valproate | Drug | Valproate 300 mg/die |
|
|
| Standard dose valproate | Drug | Valproate 600 mg/die |
|
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| Low dose zonisamide | Drug | Zonisamide 150 mg/die |
|
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| Standard dose zonisamide | Drug | Zonisamide 300 mg/die |
|
|
| Low dose oxcarbazepine | Drug | Oxcarbazepine 600 mg/die |
|
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| Standard dose oxcarbazepine | Drug | Oxcarbazepine 1200 mg/die |
|
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| Low dose topiramate | Drug | Topiramate 100 mg/die |
|
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| Standard dose topiramate | Drug | Topiramate 200 mg/die |
|
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| Low dose lamotrigine | Drug | Lamotrigine 100 mg/die |
|
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| Standard dose lamotrigine | Drug | Lamotrigine 200 mg/die |
|
|
| Low dose gabapentin | Drug | Gabapentin 450 mg/die |
|
|
| Standard dose gabapentin | Drug | Gabapentin 900 mg/die |
|
|
The score of the seven Patients Satisfaction Questionnaire 18 items (PSQ-18) subscales (general satisfaction, technical quality, interpersonal manner, communication, financial aspects, time spent with doctor, accessibility and convenience) at the last visit; the score of each subscale ranges from 1 (worst) to 5 (best).
| 12 months |
| QoLIE-31, Italian Version | QoLIE-31 measures the quality of life of patients with epilepsy (range 0-100, where 0 corresponds to the worst quality of life and 100 corresponds to the best), at the end of study visit. | 12 months |
| Health Care Resources Utilization. | The mean daily patient's cost of health care resources consumed for the management of epilepsy during the first 12 months of the study. | 12 months |
| 6790275 | Background | Proposal for revised clinical and electroencephalographic classification of epileptic seizures. From the Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia. 1981 Aug;22(4):489-501. doi: 10.1111/j.1528-1157.1981.tb06159.x. No abstract available. |
| 24730690 | Background | Fisher RS, Acevedo C, Arzimanoglou A, Bogacz A, Cross JH, Elger CE, Engel J Jr, Forsgren L, French JA, Glynn M, Hesdorffer DC, Lee BI, Mathern GW, Moshe SL, Perucca E, Scheffer IE, Tomson T, Watanabe M, Wiebe S. ILAE official report: a practical clinical definition of epilepsy. Epilepsia. 2014 Apr;55(4):475-82. doi: 10.1111/epi.12550. Epub 2014 Apr 14. |
| 11971128 | Background | Gilliam F. Optimizing health outcomes in active epilepsy. Neurology. 2002 Apr 23;58(8 Suppl 5):S9-20. doi: 10.1212/wnl.58.8_suppl_5.s9. |
| 21429248 | Background | Maguire M, Marson AG, Ramaratnam S. Epilepsy (partial). BMJ Clin Evid. 2010 Jun 28;2010:1214. |
| 21242496 | Background | Perucca P, Jacoby A, Marson AG, Baker GA, Lane S, Benn EK, Thurman DJ, Hauser WA, Gilliam FG, Hesdorffer DC. Adverse antiepileptic drug effects in new-onset seizures: a case-control study. Neurology. 2011 Jan 18;76(3):273-9. doi: 10.1212/WNL.0b013e318207b073. |
| FG001 | Standard Dose | Dosage is in mg: standard dose carbamazepine 600; standard dose levetiracetam 1000; standard dose valproate, 600; standard dose zonisamide 300; standard dose oxcarbazepine 1200; standard dose topiramate, 200; standard dose lamotrigine, 200; standard dose gabapentin 900. Study drugs are in form of tablets for daily administration. Study drug administration duration is 12 months. The choice of the drug is left to the caring physician's discretion but it must be limited to the AEDs marketed for monotherapy use. All the study drugs will be used according to the respective SPCs, which will be sent by the promoter to all the study investigators. Standard dose carbamazepine: Carbamazepine 600 mg/die Standard dose levetiracetam: Levetiracetam 1000 mg/die Standard dose valproate: Valproate 600 mg/die Standard dose zonisamide: Zonisamide 300 mg/die Standard dose oxcarbazepine: Oxcarbazepine 1200 mg/die Standard dose topiramate: Topiramate 200 mg/die Standard dose lamotrigine: Lamotrigine 200 mg/die Standard dose gabapentin: Gabapentin 900 mg/die |
| COMPLETED |
|
| NOT COMPLETED |
|
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | Low Dose | Dosage is in mg: low dose carbamazepine, 300 ; low dose levetiracetam, 500; low dose valproate, 300; low dose zonisamide, 150; low dose oxcarbazepine, 600; low dose topiramate, 100; low dose lamotrigine, 100; low dose gabapentin, 450. Study drugs are in form of tablets for daily administration. Study drug administration duration is 12 months. The choice of the drug is left to the caring physician's discretion but it must be limited to the AEDs marketed for monotherapy use. All the study drugs will be used according to the respective SPCs, which will be sent by the promoter to all the study investigators. Low dose carbamazepine: Carbamazepine, 300 mg/die Low dose levetiracetam: Levetiracetam 500 mg/die Low dose valproate: Valproate 300 mg/die Low dose zonisamide: Zonisamide 150 mg/die Low dose oxcarbazepine: Oxcarbazepine 600 mg/die Low dose topiramate: Topiramate 100 mg/die Low dose lamotrigine: Lamotrigine 100 mg/die Low dose gabapentin: Gabapentin 450 mg/die |
| BG001 | Standard Dose | Dosage is in mg: standard dose carbamazepine 600; standard dose levetiracetam 1000; standard dose valproate, 600; standard dose zonisamide 300; standard dose oxcarbazepine 1200; standard dose topiramate, 200; standard dose lamotrigine, 200; standard dose gabapentin 900. Study drugs are in form of tablets for daily administration. Study drug administration duration is 12 months. The choice of the drug is left to the caring physician's discretion but it must be limited to the AEDs marketed for monotherapy use. All the study drugs will be used according to the respective SPCs, which will be sent by the promoter to all the study investigators. Standard dose carbamazepine: Carbamazepine 600 mg/die Standard dose levetiracetam: Levetiracetam 1000 mg/die Standard dose valproate: Valproate 600 mg/die Standard dose zonisamide: Zonisamide 300 mg/die Standard dose oxcarbazepine: Oxcarbazepine 1200 mg/die Standard dose topiramate: Topiramate 200 mg/die Standard dose lamotrigine: Lamotrigine 200 mg/die Standard dose gabapentin: Gabapentin 900 mg/die |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median | Inter-Quartile Range | years |
| |||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
| ||||||||||||||||
| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
| |||||||||||||||
| Region of Enrollment | Number | participants |
| ||||||||||||||||
| Type of seizures | Included were only focal seizures based on ILAE classification | Count of Participants | Participants |
| |||||||||||||||
| Seizure frequency | Count of Participants | Participants |
| ||||||||||||||||
| Etiology | Count of Participants | Participants |
| ||||||||||||||||
| PSQ-18 | Patients Satisfaction Questionnaire 18 items (PSQ-18) measures various aspects related to satisfaction in disease management (general satisfaction, technical quality, interpersonal manner, communication, financial aspects, time spent with doctors, accessibility and convenience), each with a range from 1 to 5, where 1 indicates the least possible satisfaction, 5 the greatest. | Median | Inter-Quartile Range | units on a scale |
| ||||||||||||||
| Qolie 31 | The Quality-of-Life in Epilepsy Inventory (QOLIE-31) measures the quality of life in patients with epilepsy (range 0-100, where 0 indicates the worst quality of life, 100 the best). | Median | Inter-Quartile Range | units on a scale |
| ||||||||||||||
| Time from first symptoms to diagnosis | Median | Inter-Quartile Range | months |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Treatment Failure | The proportion of patients experiencing a treatment failure motivated by the need to change the assigned dose or the assigned drug for seizure relapse during the follow-up. All proportions are reported as percentages. | Posted | Count of Participants | Participants | 12 months |
|
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| ||||||||||||||||||||||||||||||
| Secondary | Drug-related Adverse Events | the proportion of patients experiencing a treatment failure motivated by intolerable drug-related adverse events during the follow-up; | Posted | Count of Participants | Participants | 12 months |
| ||||||||||||||||||||||||||||||||
| Secondary | PSQ-18, Italian Version | The score of the seven Patients Satisfaction Questionnaire 18 items (PSQ-18) subscales (general satisfaction, technical quality, interpersonal manner, communication, financial aspects, time spent with doctor, accessibility and convenience) at the last visit; the score of each subscale ranges from 1 (worst) to 5 (best). | Posted | Median | Inter-Quartile Range | units on a scale | 12 months |
| |||||||||||||||||||||||||||||||
| Secondary | QoLIE-31, Italian Version | QoLIE-31 measures the quality of life of patients with epilepsy (range 0-100, where 0 corresponds to the worst quality of life and 100 corresponds to the best), at the end of study visit. | Posted | Median | Inter-Quartile Range | units on a scale | 12 months |
| |||||||||||||||||||||||||||||||
| Secondary | Health Care Resources Utilization. | The mean daily patient's cost of health care resources consumed for the management of epilepsy during the first 12 months of the study. | Posted | Median | Inter-Quartile Range | euro | 12 months |
|
12 months
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Low Dose | Dosage is in mg: low dose carbamazepine, 300; low dose levetiracetam, 500; low dose valproate, 300; low dose zonisamide, 150; low dose oxcarbazepine, 600; low dose topiramate, 100; low dose lamotrigine, 100; low dose gabapentin, 450; low dose lacosamide 100 mg. Study drugs are in form of tablets for daily administration. Study drug administration duration is 12 months. The choice of the drug is left to the caring physician's discretion but it must be limited to the AEDs marketed for monotherapy use. All the study drugs will be used according to the respective SPCs, which will be sent by the promoter to all the study investigators. The arm/group "low dose" includes all the interventions listed above which correspond to low dose of each antiepileptic monotherapy. All the results were grouped by arm/group. In the adverse events tables all the single drugs were specified in each arm/group. The aim of this study was to compare the low dose arm/group versus the standard dose arm/group independently from the specific intervention/drug prescribed by the neurologist. Randomization was done by dose and not by drug. The drug has been chosen by the treating physician. | 0 | 29 | 2 | 29 | 9 | 29 |
| EG001 | Standard Dose | Dosage is in mg: standard dose carbamazepine 600; standard dose levetiracetam 1000; standard dose valproate, 600; standard dose zonisamide 300; standard dose oxcarbazepine 1200; standard dose topiramate, 200; standard dose lamotrigine, 200; standard dose gabapentin 900; standard dose lacosamide 200 mg. Study drugs are in form of tablets for daily administration. Study drug administration duration is 12 months. The choice of the drug is left to the caring physician's discretion but it must be limited to the AEDs marketed for monotherapy use. All the study drugs will be used according to the respective SPCs, which will be sent by the promoter to all the study investigators. The arm/group "standard dose" includes all the interventions listed above which correspond to standard dose of each antiepileptic monotherapy. All the results were grouped by arm/group. In the adverse events tables all the single drugs were specified in each arm/group. The aim of this study was to compare the low dose arm/group versus the standard dose arm/group independently from the specific intervention/drug prescribed by the neurologist. Randomization was done by dose and not by drug. The drug has been chosen by the treating physician. | 0 | 29 | 1 | 29 | 11 | 29 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| HEART FAILURE | Cardiac disorders | Systematic Assessment | Participant treated with Levetiracetam 500 mg (low dose) |
| |
| DYSARTHRIA | Nervous system disorders | Systematic Assessment | Participant treated with Levetiracetam 500 mg (low dose) |
| |
| OTHER, SPECIFY | Cardiac disorders | Systematic Assessment | Participant treated with Levetiracetam 500 mg (low dose) |
| |
| status epilepticus | Nervous system disorders | Systematic Assessment | Participant treated with Lacosamide 200 mg (standard dose) |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| IRRITABILITY | Psychiatric disorders | Systematic Assessment | One participant was treated with levetiracetam 500 mg (low dose); two participants were treated with levetiracetam 1000 mg (standard dose) |
| |
| Fatigue | Nervous system disorders | Systematic Assessment | One participants was treated with levetiracetam 500 mg (low dose), one was treated with oxcarbazepine 600 mg (low dose); two participants were treated with levetiracetam 1000 mg (standard dose), one with carbamazepine 600 mg (standard dose) |
| |
| Dizziness | Nervous system disorders | Systematic Assessment | One participant was treated with oxcarbazepine 600 mg (low dose), one with lacosamide 100 mg (low dose). |
| |
| rash maculo-papular | Eye disorders | Systematic Assessment | One participant was treated with carbamazepine 600 mg (standard dose) and one with oxcarbazepine 1200 mg (standard dose) |
| |
| Somnolence | Nervous system disorders | Systematic Assessment | 2 participants were treated with levetiracetam 500 mg, 1 with oxcarbazepine 600 mg and 1 with lamotrigine 100 mg (low dose); 2 participants were treated with oxcarbazepine 1200 mg, 1 with levetiracetam 1000 mg, 1 with lacosamide 200 mg (standard). |
|
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Giorgia Giussani | Istituto di Ricerche Farmacologiche Mario Negri IRCCS | 0239014604 | giorgia.giussani@marionegri.it |
| Mar 24, 2025 |
| Prot_SAP_000.pdf |
| ID | Term |
|---|---|
| D004828 | Epilepsies, Partial |
| D004827 | Epilepsy |
| ID | Term |
|---|---|
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
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| ID | Term |
|---|---|
| D002220 | Carbamazepine |
| D000077287 | Levetiracetam |
| D014635 | Valproic Acid |
| D000078305 | Zonisamide |
| D000078330 | Oxcarbazepine |
| D000077236 | Topiramate |
| D000077213 | Lamotrigine |
| D000077206 | Gabapentin |
| ID | Term |
|---|---|
| D003984 | Dibenzazepines |
| D006575 | Heterocyclic Compounds, 3-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D000081 | Acetamides |
| D000577 | Amides |
| D009930 | Organic Chemicals |
| D000085 | Acetates |
| D000144 | Acids, Acyclic |
| D002264 | Carboxylic Acids |
| D011760 | Pyrrolidinones |
| D011759 | Pyrrolidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D010421 | Pentanoic Acids |
| D014631 | Valerates |
| D005232 | Fatty Acids, Volatile |
| D005227 | Fatty Acids |
| D008055 | Lipids |
| D013449 | Sulfonamides |
| D013450 | Sulfones |
| D013457 | Sulfur Compounds |
| D007555 | Isoxazoles |
| D001393 | Azoles |
| D005632 | Fructose |
| D006601 | Hexoses |
| D009005 | Monosaccharides |
| D000073893 | Sugars |
| D002241 | Carbohydrates |
| D007661 | Ketoses |
| D014227 | Triazines |
| D000588 | Amines |
| D005680 | gamma-Aminobutyric Acid |
| D000613 | Aminobutyrates |
| D002087 | Butyrates |
| D003509 | Cyclohexanecarboxylic Acids |
| D000146 | Acids, Carbocyclic |
| D003510 | Cyclohexanes |
| D003516 | Cycloparaffins |
| D006840 | Hydrocarbons, Alicyclic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D000596 | Amino Acids |
| D000602 | Amino Acids, Peptides, and Proteins |
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| Technical quality |
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| Interpersonal manner |
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| Communication |
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| Financial aspects |
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| Time spent with doctors |
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| Accessibility and convenience |
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