PharmacogeneticsPhase 1APSEPNCT01259973
Typical Versus Atypical Antipsychotics; Occupation of Striatal Receptors and the Appearance of Extrapyramidal Symptomatology, in Healthy Volunteers
A Phase 1 study testing Risperidone and Haloperidol in people with Pharmacogenetics and Healthy, run by Hospital Clinic of Barcelona at 2 sites in Spain.
Trial summary
The purpose of this study is to determine in healthy volunteers treated with typical or atypical antipsychotics -AP-, the relationship between genetic polymorphisms in cytochrome genes CYP2D6 (*3, *4, *5, *6 and Nxn) and CYP3A5 (*3) with antipsychotic pharmacokinetics, occupancy of striatal dopaminergic receptors and… Read more about this study
- Who is it for?
- Ages 18 to 30 yearsHealthy volunteers can take part
- Conditions the study is for
- Pharmacogenetics, Healthy
- What is being tested?
- Risperidone and Haloperidol
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 24 participants
- Where
- 2 sitesSpain
- Study dates
- Feb 2011to Dec 2011
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 30 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- Subjects of both genders with ages between 18-30 years.
- Subjects with normal values of clinical history and physical exploration.
- Subjects without evidence of significant disease, organic or psychiatric, according to anamnesis (medical history), physical exploration and complementary tests.
- Subjects with normal values of laboratory tests (hemogram and biochemical tests).
- Subjects with normal values of vital signs (Blood pressure, Heart rate, Temperature) and Electrocardiography.
- Female subjects must be using safe contraceptive methods, different from oral contraceptives.
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- Subjects could not have taken part in other clinical trials during the three previous months before to the beginning of this study.
- Subjects could not have given blood during four weeks before the beginning of this study.
- Subjects must accept freely their participation, with written informed consent.
- After previous genotyping for CYP2D6 and CYP3A4/A5 genes, chosen participants must have one of the following genotypes of interest for this study:
- poor metabolizers (PM) CYP2D6*
- poor metabolizers (PM) CYP3A5**
- extensive metabolizers (EM) CYP2D6/CYP3A
- ultrarapid metabolizers (UM) CYP2D6*
- Subjects must accept to undergo neuroimaging (SPECT).
Who cannot join
- Subjects with previous medical history of alcoholism or drug dependency.
- Subjects with clinical history of allergy, idiosyncrasy or hypersensitivity to drugs.
- Subjects with clinical history or current treatment with drugs whose metabolism could interfere in the action of CYP2D6 and CYP3A5 cytochromes, particularly if they are not able to give up the treatment for a period of 3-4 weeks before the beginning of the study and during its execution.
- Subjects with clinical history or current consumption of drugs that could interfere in the action of CYP2D6 and CYP3A5 cytochromes (St John's wort, cruciferae, grapefruit ...), particularly if they are not able to give up their consumption for a period of 3-4 weeks before the beginning of the study and during its execution.
- Subjects with contraindications for antipsychotic treatments due to: familiar/clinical history of hypersensitivity to antipsychotic drugs, deep depression of central nervous system, coma, Parkinson's disease.
- Pregnant women, women in breastfeeding period or women that do not use safe contraceptive methods, different from oral contraception.
- Subjects with positive serology for hepatitis B virus (HBV), hepatitis C virus (HCV) or human immunodeficiency virus (HIV).
- Subjets with positive test in urine for ethanol, cannabis, cocaine, amphetamines, benzodiazepines and/or opiates.
Trial locations and contacts
2 sites in 1 country.
Spain2 sites
Hospital de la Santa Creu i Sant Pau
Barcelona, Barcelona, 08025
Hospital Clinic of Barcelona
Barcelona, Barcelona, 08036
About this study
Official title: Phase I Clinical Trial. Study of the Impact of Pharmacogenetic Markers in Predicting the Appearance of Extrapyramidal Symptomatology After the Treatment With Typical vs. Atypical Antipsychotics, in Healthy Volunteers
The purpose of this study is to determine in healthy volunteers treated with typical or atypical antipsychotics -AP-, the relationship between genetic polymorphisms in cytochrome genes CYP2D6 (*3, *4, *5, *6 and Nxn) and CYP3A5 (*3) with antipsychotic pharmacokinetics, occupancy of striatal dopaminergic receptors and the appearance of extrapyramidal symptomatology -EPS-.
Read the detailed description
Objective:
The preliminary results indicate that pharmacological factors (AP, dose and drug availability depending on cytochrome activity) are risk factors for AP-induced EPS.
In this clinical trial, the investigators will study, in healthy volunteers, the effects on pharmacokinetics, occupancy of striatal dopaminergic receptors and the appearance of EPS according to genetic polymorphisms in cytochrome genes CYP2D6 (*3, *4, *5, *6 and Nxn) and CYP3A5 (*3). The investigators will compare a typical AP (Haloperidol) with an atypical AP (Risperidone), both of which are metabolized by CYP2D6 and CYP3A5.
Specific objectives:
- Study the relationship between genetic polymorphisms in cytochrome genes CYP2D6 (*3, *4, *5, *6 and Nxn) and CYP3A5 (*3) and plasmatic levels of Haloperidol and Risperidone.
- Study the relationship between genetic polymorphisms in cytochrome genes CYP2D6 (*3, *4, *5, *6 and Nxn) and CYP3A5 (*3) and the grade of occupancy of striatal dopaminergic receptors with Haloperidol and Risperidone.
- Study the relationship between plasmatic levels of Haloperidol and Risperidone and the grade of occupancy of striatal dopaminergic receptors with these two drugs.
- Study the relationship between genetic polymorphisms in cytochrome genes CYP2D6 (*3, *4, *5, *6 and Nxn) and CYP3A5 (*3), plasmatic levels of Haloperidol and Risperidone, and the grade of occupancy of striatal dopaminergic receptors with these two drugs, with the appearance of AP-induced EPS.
Methodology:
From a cohort of 200 healthy volunteers (males and females with ages between 18-30 years), previously genotyped for CYP2D6 and CYP3A5 genes (from January to June 2010), the investigators have selected subjects depending on their metabolizer phenotype (poor metabolizers, intermediate metabolizers, extensive metabolizers and ultrarapid metabolizers) by DNA extraction from whole blood samples and SNP detection approaches.
Finally, the investigators will include the following four phenotypical groups with 6-8 subjects in each of the groups (a total of N=32 subjects, approximately):
- poor metabolizers (PM) CYP2D6*
- poor metabolizers (PM) CYP3A5**
- extensive metabolizers (EM) CYP2D6/CYP3A
- ultrarapid metabolizers (UM) CYP2D6*
The design corresponds to a three ways cross-over randomized and double-blind trial, with a wash-out period of one week among each treatment.
Measurements of occupancy of striatal dopaminergic receptors will be done by single photon emission computed tomography -SPECT- and SEP will be measured based on the Simpson-Angus scale and actimetry.
General protocol:
One week before their participation in the trial, volunteers will undergo clinical and physical explorations (blood test, electrocardiography, urine drug screening...) and will be trained in the different tests of the study (to minimize differences regarding to experience).
During the study, participants will be treated with a single dose of an AP drug (5mg Haloperidol or 2.5mg Risperidone) or a single dose of placebo (2.5mL physiological serum).
Plasma levels will be measured at +0.5h, +1h, +2h, +4h, +6h, +8h and +12h of drug/placebo administration.
The tracer [123I]IBZM will be administered at +3h of drug/placebo administration and SPECT will be performed at +5h.
Status of EPS, as well as positive and negative AP-derived symptoms, will be measured at -1h and at different time frames post-drug/placebo administration, beginning at +3h and until +24h (depending on each Scale used).
Participants will be hospitalized for three complete days (separated between them by one wash-out week after each treatment) from 8.00h to 8.00h of the following day at Phase I Unit of "Hospital de Sant Pau i de la Santa Creu", in Barcelona, in order to monitor the results obtained after each treatment. During their hospitalization, participants will be given food and drink every two hours.
This clinical trial will start in February 2011 and finish in November 2011.
- Conditions
- Pharmacogenetics, Healthy
- Being tested
- Risperidone, Placebo, Haloperidol
- Keywords
- Pharmacogenetics, Antipsychotics, Extrapyramidal Symptoms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
RisperidoneDrug
1 single dose of 2.5mg masked in 250 mL of peach juice, for 1 day. Oral administration.
PlaceboDrug
1 single dose of 2.5mL physiological serum masked in 250 mL of peach juice, for 1 day. Oral administration.
HaloperidolDrug
1 single dose of 5mg masked in 250 mL of peach juice, for 1 day. Oral administration.
| Study group | Role | What they receive |
|---|---|---|
| Risperidone | Experimental | Not described Receives: Drug: Risperidone |
| Placebo | Placebo comparator | Not described Receives: Drug: Placebo |
| Haloperidol | Experimental | Not described Receives: Drug: Haloperidol |
What is being measured
The primary outcome is the main question the study is designed to answer.
Changes among genotypes in 24 h monitored Haloperidol and Risperidone pharmacokinetics
Through a catheter, blood samples will be obtained at different time frames. Samples will be kept with anticoagulants and centrifuged immediately to separate the plasmatic fraction, which will be kept at -70ºC. In order to determine the concentration of Haloperidol (and reduced Haloperidol) and Risperidone (and 9-OH Risperidone), high performance liquid chromatography -HPLC- will be achieved.
A poblation-pharmacokinetic model of the two AP drugs will be designed, and drug vs. placebo treatment results will be compared.
Parameters determined: AUC, Cmax, Tmax, T(1/2), Vd, CL and MRT.
Measured: + 0.5h, +1h, +2h, +4h, +6h, +8h, +12h and +24h post-treatment
Changes from placebo in occupancy of striatal dopaminergic receptors by Haloperidol and Risperidone at 5h
The tracer [123I]IBZM, a dopaminergic antagonist, will be administered by means of intravenous injection (at +3h post-treatment) at the opposite arm from which blood samples will be obtained. Neuroimaging will be done in SPECT gamma chambers and images will be quantified comparing drug vs. placebo treatment results.
Parameters determined: Average Count Striatum and Count Occipital Cortex, Specific Uptake Ratio, D2 Occupational Receptor.
100% of volunteers will undergo SPECT after placebo treatment and, among them, 50% after Haloperidol treatment and 50% after Risperidone treatment.
Measured: +3h post-treatment: tracer injection. +5h post-treatment: image acquisition
Changes from baseline in Extrapyramidal Symptomatology (EPS) at 3h, measured by Simpson-Angus Rating Scale (SARS)and Barnes Akathisia Rating Scale (BARS), and during 24 h, measured by actimetry
AP-induced EPS measured by:
- Heteroadministered scales:
- Simpson-Angus Rating Scale (SARS). Assesses drug-induced parkinsonism (tremor, hypokinesia, rigidity, and postural instability).
- Barnes Akathisia Rating Scale (BARS). Assesses drug-induced akathisia (restlessness and inability to sit still).
- Actimetry: Continuous recording of movement, in terms of count of movements per minute, by using a wrist actimeter (model AW4) fitted to the arm not used for writing.
Differences observed by comparing EPS after drug vs. placebo treatment will be considered.
Measured: Heteroadministered scales will be measured at -1h pre-treatment (basal level) and at +3h. Actimetry will be measured continuosly since -1h pre-treatment until +24h
Secondary outcomes (5)
Changes from baseline in Positive and Negative Symptomatology at 3h, measured by Brief Psychiatric Rating Scale (BPRS) and Scale for the Assessment of Negative Symptoms (SANS), and at 24h, measured by Subjective Deficit Syndrome Scale (SDSS)
AP-induced positive/negative symptoms measured by:
- Brief Psychiatric Rating Scale (BPRS). Heteroadministered and semi structured interview (20 min) to determine hostility, suspiciousness, hallucination, and grandiosity.
- Scale for the Assessment of Negative Symptoms (SANS). Heteroadministered interview (20 min) to determine affective blunting, alogia, avolition/apathy, anhedonia/asociality and disturbance of attention.
- Subjective Deficit Syndrome Scale (SDSS). Autoadministered interview (20 min) to determine emotionless.
Drug vs. placebo treatment will be compared.
Measured: BPRS and SANS scales will be measured at -1h pre-treatment (basal level) and at +3h. SDSS scale will be measured at -1h pre-treatment (basal level) and at +24h
Changes from baseline in 24h prolactin kinetics
Blood samples analyzed will be the ones obtained for measuring plasmatic levels of antipsychotic drugs.
Plasmatic levels of prolactin will be measured by enzymatic immunoassay approaches.
Differences observed after drug vs. placebo treatment will be compared.
Measured: At -1h pre-treatment (basal level) and at +0.5h, +1h, +2h, +4h, +6h, +8h, +12h and +24h post-treatment
Changes from baseline in anticholinergic activity through Whole Saliva Test (WST) during 8h
Salivette Containers (from Sarstedt) will be used to determine the saliva flow accumulated during 2 min.
Differences observed after drug vs. placebo treatment will be compared.
Measured: At -1h pre-treatment (basal level) and at +1h, +2h, +4h, +6h and +8h post-treatment
Changes from baseline in cardiovascular effects through Orthostatism measurement during 8h
In order to determine orthostatic hypotension, Systolic Arterial Pressure (SAP), Diastolic Arterial Pressure (DAP) and Cardiac frequency (CF) will be measured both after 3 min in supine position and after 3 min in erect position.
Differences observed after drug vs. placebo treatment will be compared.
Measured: At -1h pre-treatment (basal level) and at +1h, +2h, +4h, +6h and +8h post-treatment
Changes from baseline in sedative effects during 8h
AP-induced sedative effects measured by:
- Psychomotricity
- Flicker-Fusion Critical Frequency (FFCF). Detection of a flickering/stable red light.
- Simple Reaction Time (SRT). Detection of a simple red light switched on/off.
- Digit Symbol Substitution Test (DSST). Measures the amount of digits substituted correctly by its corresponding symbol.
- Tapping Test (TT). Average of tappings per second.
- Pupilometry. Detect pupil's response in basal conditions.
- Visual Analog Scales (VAS). Detect agreement to a statement by indicating a position within two end-points.
Measured: At -1h pre-treatment (basal level) and at +1h, +2h, +4h, +6h and +8h post-treatment
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Dec 2010 (estimated)
- Study startFeb 2011
- Primary completionNov 2011 (estimated)
- Study completionDec 2011 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (10)Papers the sponsor has linked to this study.
- Other trials for PharmacogeneticsStudies of the same condition, open and under way.
- More trials run by Hospital Clinic of BarcelonaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 24 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Hospital Clinic of Barcelona
- Sponsor type
- University, hospital or other
- Collaborators
- Fundacion Clinic per a la Recerca Biomédica, Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau, University of Barcelona
- Investigators
- Miquel Bernardo Arroyo, Head of Psychiatry, Principal investigator, Hospital Clinic of BarcelonaAmalia Lafuente Flo, Pharmacology professor, Study director, Dept. Pathologic Anatomy, Pharmacology and Microbiology, Medical Service, UB University of BarcelonaSergi Mas Herrero, Pos-doc assistant professor, Study chair, Dept. Pathologic Anatomy, Pharmacology and Microbiology, Medical Service, UB University of BarcelonaPatricia Gassó Astorga, Pos-doc associated professor, Study chair, Dept. Pathologic Anatomy, Pharmacology and Microbiology, Medical Service, UB University of BarcelonaGemma Trias Lafuente, Psychologist, Study chair, Dept. Pathologic Anatomy, Pharmacology and Microbiology, Medical Service, UB University of BarcelonaEva Ferrando Martorell, Pre-doc, Study chair, Dept. Pathologic Anatomy, Pharmacology and Microbiology, Medical Service, UB University of BarcelonaRosa M Antonijoan, Clinical Pharmacologist, Study chair, Clinical Pharmacology Service, Hospital de la Santa Creu i Sant PauAnalía Azaro, Clinical Pharmacologist, Study chair, Clinical Pharmacology Service, Hospital de la Santa Creu i Sant Pau
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01259973
- Sponsor's protocol ID
- TRA-065
- Other IDs
- 2009-016519-40, TRA-065, 2009
- Acronym
- APSEP
- Status last verified
- Jan 2011
- First submitted
- 13 Dec 2010
- Last updated
- 18 Apr 2011
- Results posted
- No
- Data monitoring committee
- No
Publications
Lafuente A, Bernardo M, Mas S, Crescenti A, Aparici M, Gasso P, Catalan R, Mateos JJ, Lomena F, Parellada E. Dopamine transporter (DAT) genotype (VNTR) and phenotype in extrapyramidal symptoms induced by antipsychotics. Schizophr Res. 2007 Feb;90(1-3):115-22. doi: 10.1016/j.schres.2006.09.031. Epub 2006 Dec 5.
PubMed 17150335Lafuente A, Bernardo M, Mas S, Crescenti A, Aparici M, Gasso P, Deulofeu R, Mane A, Catalan R, Carne X. Polymorphism of dopamine D2 receptor (TaqIA, TaqIB, and-141C Ins/Del) and dopamine degradation enzyme (COMT G158A, A-278G) genes and extrapyramidal symptoms in patients with schizophrenia and bipolar disorders. Psychiatry Res. 2008 Nov 30;161(2):131-41. doi: 10.1016/j.psychres.2007.08.002. Epub 2008 Oct 15.
PubMed 18922583Crescenti A, Mas S, Gasso P, Parellada E, Bernardo M, Lafuente A. Cyp2d6*3, *4, *5 and *6 polymorphisms and antipsychotic-induced extrapyramidal side-effects in patients receiving antipsychotic therapy. Clin Exp Pharmacol Physiol. 2008 Jul;35(7):807-11. doi: 10.1111/j.1440-1681.2008.04918.x. Epub 2008 Mar 12.
PubMed 18346175Gasso P, Mas S, Bernardo M, Alvarez S, Parellada E, Lafuente A. A common variant in DRD3 gene is associated with risperidone-induced extrapyramidal symptoms. Pharmacogenomics J. 2009 Dec;9(6):404-10. doi: 10.1038/tpj.2009.26. Epub 2009 Jun 9.
PubMed 19506579Gasso P, Mas S, Crescenti A, Alvarez S, Parramon G, Garcia-Rizo C, Parellada E, Bernardo M, Lafuente A. Lack of association between antipsychotic-induced extrapyramidal symptoms and polymorphisms in dopamine metabolism and transport genes. Psychiatry Res. 2010 Jan 30;175(1-2):173-5. doi: 10.1016/j.psychres.2009.07.006. Epub 2009 Nov 5.
PubMed 19892410Ingelman-Sundberg M, Sim SC, Gomez A, Rodriguez-Antona C. Influence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic, pharmacoepigenetic and clinical aspects. Pharmacol Ther. 2007 Dec;116(3):496-526. doi: 10.1016/j.pharmthera.2007.09.004. Epub 2007 Oct 9.
PubMed 18001838Mauri MC, Volonteri LS, Colasanti A, Fiorentini A, De Gaspari IF, Bareggi SR. Clinical pharmacokinetics of atypical antipsychotics: a critical review of the relationship between plasma concentrations and clinical response. Clin Pharmacokinet. 2007;46(5):359-88. doi: 10.2165/00003088-200746050-00001.
PubMed 17465637Zanger UM, Turpeinen M, Klein K, Schwab M. Functional pharmacogenetics/genomics of human cytochromes P450 involved in drug biotransformation. Anal Bioanal Chem. 2008 Nov;392(6):1093-108. doi: 10.1007/s00216-008-2291-6. Epub 2008 Aug 10.
PubMed 18695978Catafau AM, Penengo MM, Nucci G, Bullich S, Corripio I, Parellada E, Garcia-Ribera C, Gomeni R, Merlo-Pich E; Barcelona Clinical Imaging in Psychiatry Group. Pharmacokinetics and time-course of D(2) receptor occupancy induced by atypical antipsychotics in stabilized schizophrenic patients. J Psychopharmacol. 2008 Nov;22(8):882-94. doi: 10.1177/0269881107083810. Epub 2008 Feb 28.
PubMed 18308793Mas S, Gasso P, Fernandez de Bobadilla R, Arnaiz JA, Bernardo M, Lafuente A. Secondary nonmotor negative symptoms in healthy volunteers after single doses of haloperidol and risperidone: a double-blind, crossover, placebo-controlled trial. Hum Psychopharmacol. 2013 Nov;28(6):586-93. doi: 10.1002/hup.2350. Epub 2013 Oct 7.
PubMed 24519692
Study at a glance
From the registry record, last updated by the sponsor on 18 Apr 2011. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase I Clinical Trial. Study of the Impact of Pharmacogenetic Markers in Predicting the Appearance of Extrapyramidal Symptomatology After the Treatment With Typical vs. Atypical Antipsychotics, in Healthy Volunteers
- ClinicalTrials.gov ID
- NCT01259973
- Acronym / sponsor ID
- APSEP / TRA-065
- Conditions
- Pharmacogenetics, Healthy
- Keywords
- Pharmacogenetics, Antipsychotics, Extrapyramidal Symptoms
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 24 participants (estimated)
- Lead sponsor
- Hospital Clinic of BarcelonaUniversity, hospital or other
- Collaborators
- Fundacion Clinic per a la Recerca Biomédica, Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau, University of Barcelona
- Study start
- Feb 2011
- Primary completion
- Nov 2011 (estimated)
- Study completion
- Dec 2011 (estimated)
- First posted
- 15 Dec 2010 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of this study is to determine in healthy volunteers treated with typical or atypical antipsychotics -AP-, the relationship between genetic polymorphisms in cytochrome genes CYP2D6 (*3, *4, *5, *6 and Nxn) and CYP3A5 (*3) with antipsychotic pharmacokinetics, occupancy of striatal dopaminergic receptors and the appearance of extrapyramidal symptomatology -EPS-.
Detailed description
Objective:
The preliminary results indicate that pharmacological factors (AP, dose and drug availability depending on cytochrome activity) are risk factors for AP-induced EPS.
In this clinical trial, the investigators will study, in healthy volunteers, the effects on pharmacokinetics, occupancy of striatal dopaminergic receptors and the appearance of EPS according to genetic polymorphisms in cytochrome genes CYP2D6 (*3, *4, *5, *6 and Nxn) and CYP3A5 (*3). The investigators will compare a typical AP (Haloperidol) with an atypical AP (Risperidone), both of which are metabolized by CYP2D6 and CYP3A5.
Specific objectives:
- Study the relationship between genetic polymorphisms in cytochrome genes CYP2D6 (*3, *4, *5, *6 and Nxn) and CYP3A5 (*3) and plasmatic levels of Haloperidol and Risperidone.
- Study the relationship between genetic polymorphisms in cytochrome genes CYP2D6 (*3, *4, *5, *6 and Nxn) and CYP3A5 (*3) and the grade of occupancy of striatal dopaminergic receptors with Haloperidol and Risperidone.
- Study the relationship between plasmatic levels of Haloperidol and Risperidone and the grade of occupancy of striatal dopaminergic receptors with these two drugs.
- Study the relationship between genetic polymorphisms in cytochrome genes CYP2D6 (*3, *4, *5, *6 and Nxn) and CYP3A5 (*3), plasmatic levels of Haloperidol and Risperidone, and the grade of occupancy of striatal dopaminergic receptors with these two drugs, with the appearance of AP-induced EPS.
Methodology:
From a cohort of 200 healthy volunteers (males and females with ages between 18-30 years), previously genotyped for CYP2D6 and CYP3A5 genes (from January to June 2010), the investigators have selected subjects depending on their metabolizer phenotype (poor metabolizers, intermediate metabolizers, extensive metabolizers and ultrarapid metabolizers) by DNA extraction from whole blood samples and SNP detection approaches.
Finally, the investigators will include the following four phenotypical groups with 6-8 subjects in each of the groups (a total of N=32 subjects, approximately):
- poor metabolizers (PM) CYP2D6*
- poor metabolizers (PM) CYP3A5**
- extensive metabolizers (EM) CYP2D6/CYP3A
- ultrarapid metabolizers (UM) CYP2D6*
The design corresponds to a three ways cross-over randomized and double-blind trial, with a wash-out period of one week among each treatment.
Measurements of occupancy of striatal dopaminergic receptors will be done by single photon emission computed tomography -SPECT- and SEP will be measured based on the Simpson-Angus scale and actimetry.
General protocol:
One week before their participation in the trial, volunteers will undergo clinical and physical explorations (blood test, electrocardiography, urine drug screening...) and will be trained in the different tests of the study (to minimize differences regarding to experience).
During the study, participants will be treated with a single dose of an AP drug (5mg Haloperidol or 2.5mg Risperidone) or a single dose of placebo (2.5mL physiological serum).
Plasma levels will be measured at +0.5h, +1h, +2h, +4h, +6h, +8h and +12h of drug/placebo administration.
The tracer [123I]IBZM will be administered at +3h of drug/placebo administration and SPECT will be performed at +5h.
Status of EPS, as well as positive and negative AP-derived symptoms, will be measured at -1h and at different time frames post-drug/placebo administration, beginning at +3h and until +24h (depending on each Scale used).
Participants will be hospitalized for three complete days (separated between them by one wash-out week after each treatment) from 8.00h to 8.00h of the following day at Phase I Unit of "Hospital de Sant Pau i de la Santa Creu", in Barcelona, in order to monitor the results obtained after each treatment. During their hospitalization, participants will be given food and drink every two hours.
This clinical trial will start in February 2011 and finish in November 2011.
Study design
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind (participant, investigator)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Risperidone | Experimental | Drug: Risperidone |
| Placebo | Placebo comparator | Drug: Placebo |
| Haloperidol | Experimental | Drug: Haloperidol |
Who may qualify
- Ages
- 18 to 30 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (15 listed)
- Subjects of both genders with ages between 18-30 years.
- Subjects with normal values of clinical history and physical exploration.
- Subjects without evidence of significant disease, organic or psychiatric, according to anamnesis (medical history), physical exploration and complementary tests.
- Subjects with normal values of laboratory tests (hemogram and biochemical tests).
- Subjects with normal values of vital signs (Blood pressure, Heart rate, Temperature) and Electrocardiography.
Key exclusion criteria (8 listed)
- Subjects with previous medical history of alcoholism or drug dependency.
- Subjects with clinical history of allergy, idiosyncrasy or hypersensitivity to drugs.
- Subjects with clinical history or current treatment with drugs whose metabolism could interfere in the action of CYP2D6 and CYP3A5 cytochromes, particularly if they are not able to give up the treatment for a period of 3-4 weeks before the beginning of the study and during its execution.
- Subjects with clinical history or current consumption of drugs that could interfere in the action of CYP2D6 and CYP3A5 cytochromes (St John's wort, cruciferae, grapefruit ...), particularly if they are not able to give up their consumption for a period of 3-4 weeks before the beginning of the study and during its execution.
- Subjects with contraindications for antipsychotic treatments due to: familiar/clinical history of hypersensitivity to antipsychotic drugs, deep depression of central nervous system, coma, Parkinson's disease.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Risperidone1 single dose of 2.5mg masked in 250 mL of peach juice, for 1 day. Oral administration. | Drug | Risperidone |
| Placebo1 single dose of 2.5mL physiological serum masked in 250 mL of peach juice, for 1 day. Oral administration. | Drug | Placebo |
| Haloperidol1 single dose of 5mg masked in 250 mL of peach juice, for 1 day. Oral administration. | Drug | Haloperidol |
Primary outcome
Changes among genotypes in 24 h monitored Haloperidol and Risperidone pharmacokinetics
Time frame: + 0.5h, +1h, +2h, +4h, +6h, +8h, +12h and +24h post-treatment
Through a catheter, blood samples will be obtained at different time frames. Samples will be kept with anticoagulants and centrifuged immediately to separate the plasmatic fraction, which will be kept at -70ºC. In order to determine the concentration of Haloperidol (and reduced Haloperidol) and Risperidone (and 9-OH Risperidone), high performance liquid chromatography -HPLC- will be achieved. A poblation-pharmacokinetic model of the two AP drugs will be designed, and drug vs. placebo treatment results will be compared. Parameters determined: AUC, Cmax, Tmax, T(1/2), Vd, CL and MRT.
Changes from placebo in occupancy of striatal dopaminergic receptors by Haloperidol and Risperidone at 5h
Time frame: +3h post-treatment: tracer injection. +5h post-treatment: image acquisition
The tracer [123I]IBZM, a dopaminergic antagonist, will be administered by means of intravenous injection (at +3h post-treatment) at the opposite arm from which blood samples will be obtained. Neuroimaging will be done in SPECT gamma chambers and images will be quantified comparing drug vs. placebo treatment results. Parameters determined: Average Count Striatum and Count Occipital Cortex, Specific Uptake Ratio, D2 Occupational Receptor. 100% of volunteers will undergo SPECT after placebo treatment and, among them, 50% after Haloperidol treatment and 50% after Risperidone treatment.
Changes from baseline in Extrapyramidal Symptomatology (EPS) at 3h, measured by Simpson-Angus Rating Scale (SARS)and Barnes Akathisia Rating Scale (BARS), and during 24 h, measured by actimetry
Time frame: Heteroadministered scales will be measured at -1h pre-treatment (basal level) and at +3h. Actimetry will be measured continuosly since -1h pre-treatment until +24h
AP-induced EPS measured by: * Heteroadministered scales: * Simpson-Angus Rating Scale (SARS). Assesses drug-induced parkinsonism (tremor, hypokinesia, rigidity, and postural instability). * Barnes Akathisia Rating Scale (BARS). Assesses drug-induced akathisia (restlessness and inability to sit still). * Actimetry: Continuous recording of movement, in terms of count of movements per minute, by using a wrist actimeter (model AW4) fitted to the arm not used for writing. Differences observed by comparing EPS after drug vs. placebo treatment will be considered.
5 secondary outcomes
Changes from baseline in Positive and Negative Symptomatology at 3h, measured by Brief Psychiatric Rating Scale (BPRS) and Scale for the Assessment of Negative Symptoms (SANS), and at 24h, measured by Subjective Deficit Syndrome Scale (SDSS)
Time frame: BPRS and SANS scales will be measured at -1h pre-treatment (basal level) and at +3h. SDSS scale will be measured at -1h pre-treatment (basal level) and at +24h
Changes from baseline in 24h prolactin kinetics
Time frame: At -1h pre-treatment (basal level) and at +0.5h, +1h, +2h, +4h, +6h, +8h, +12h and +24h post-treatment
Changes from baseline in anticholinergic activity through Whole Saliva Test (WST) during 8h
Time frame: At -1h pre-treatment (basal level) and at +1h, +2h, +4h, +6h and +8h post-treatment
Changes from baseline in cardiovascular effects through Orthostatism measurement during 8h
Time frame: At -1h pre-treatment (basal level) and at +1h, +2h, +4h, +6h and +8h post-treatment
Changes from baseline in sedative effects during 8h
Time frame: At -1h pre-treatment (basal level) and at +1h, +2h, +4h, +6h and +8h post-treatment
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Apr 2011.
- Background: PubMed 17150335Lafuente A, Bernardo M, Mas S, Crescenti A, Aparici M, Gasso P, Catalan R, Mateos JJ, Lomena F, Parellada E. Dopamine transporter (DAT) genotype (VNTR) and phenotype in extrapyramidal symptoms induced by antipsychotics. Schizophr Res. 2007 Feb;90(1-3):115-22. doi: 10.1016/j.schres.2006.09.031. Epub 2006 Dec 5.
- Background: PubMed 18922583Lafuente A, Bernardo M, Mas S, Crescenti A, Aparici M, Gasso P, Deulofeu R, Mane A, Catalan R, Carne X. Polymorphism of dopamine D2 receptor (TaqIA, TaqIB, and-141C Ins/Del) and dopamine degradation enzyme (COMT G158A, A-278G) genes and extrapyramidal symptoms in patients with schizophrenia and bipolar disorders. Psychiatry Res. 2008 Nov 30;161(2):131-41. doi: 10.1016/j.psychres.2007.08.002. Epub 2008 Oct 15.
- Background: PubMed 18346175Crescenti A, Mas S, Gasso P, Parellada E, Bernardo M, Lafuente A. Cyp2d6*3, *4, *5 and *6 polymorphisms and antipsychotic-induced extrapyramidal side-effects in patients receiving antipsychotic therapy. Clin Exp Pharmacol Physiol. 2008 Jul;35(7):807-11. doi: 10.1111/j.1440-1681.2008.04918.x. Epub 2008 Mar 12.
- Background: PubMed 19506579Gasso P, Mas S, Bernardo M, Alvarez S, Parellada E, Lafuente A. A common variant in DRD3 gene is associated with risperidone-induced extrapyramidal symptoms. Pharmacogenomics J. 2009 Dec;9(6):404-10. doi: 10.1038/tpj.2009.26. Epub 2009 Jun 9.
- Background: PubMed 19892410Gasso P, Mas S, Crescenti A, Alvarez S, Parramon G, Garcia-Rizo C, Parellada E, Bernardo M, Lafuente A. Lack of association between antipsychotic-induced extrapyramidal symptoms and polymorphisms in dopamine metabolism and transport genes. Psychiatry Res. 2010 Jan 30;175(1-2):173-5. doi: 10.1016/j.psychres.2009.07.006. Epub 2009 Nov 5.
- Background: PubMed 18001838Ingelman-Sundberg M, Sim SC, Gomez A, Rodriguez-Antona C. Influence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic, pharmacoepigenetic and clinical aspects. Pharmacol Ther. 2007 Dec;116(3):496-526. doi: 10.1016/j.pharmthera.2007.09.004. Epub 2007 Oct 9.
- Background: PubMed 17465637Mauri MC, Volonteri LS, Colasanti A, Fiorentini A, De Gaspari IF, Bareggi SR. Clinical pharmacokinetics of atypical antipsychotics: a critical review of the relationship between plasma concentrations and clinical response. Clin Pharmacokinet. 2007;46(5):359-88. doi: 10.2165/00003088-200746050-00001.
- Background: PubMed 18695978Zanger UM, Turpeinen M, Klein K, Schwab M. Functional pharmacogenetics/genomics of human cytochromes P450 involved in drug biotransformation. Anal Bioanal Chem. 2008 Nov;392(6):1093-108. doi: 10.1007/s00216-008-2291-6. Epub 2008 Aug 10.
- Background: PubMed 18308793Catafau AM, Penengo MM, Nucci G, Bullich S, Corripio I, Parellada E, Garcia-Ribera C, Gomeni R, Merlo-Pich E; Barcelona Clinical Imaging in Psychiatry Group. Pharmacokinetics and time-course of D(2) receptor occupancy induced by atypical antipsychotics in stabilized schizophrenic patients. J Psychopharmacol. 2008 Nov;22(8):882-94. doi: 10.1177/0269881107083810. Epub 2008 Feb 28.
- Derived from this study: PubMed 24519692Mas S, Gasso P, Fernandez de Bobadilla R, Arnaiz JA, Bernardo M, Lafuente A. Secondary nonmotor negative symptoms in healthy volunteers after single doses of haloperidol and risperidone: a double-blind, crossover, placebo-controlled trial. Hum Psychopharmacol. 2013 Nov;28(6):586-93. doi: 10.1002/hup.2350. Epub 2013 Oct 7.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Miquel Bernardo Arroyo, Head of Psychiatry principal investigator
Hospital Clinic of Barcelona
Amalia Lafuente Flo, Pharmacology professor study director
Dept. Pathologic Anatomy, Pharmacology and Microbiology, Medical Service, UB University of Barcelona
Sergi Mas Herrero, Pos-doc assistant professor study chair
Dept. Pathologic Anatomy, Pharmacology and Microbiology, Medical Service, UB University of Barcelona
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Risperidone and Haloperidol in people with Pharmacogenetics and Healthy, run by Hospital Clinic of Barcelona at 2 sites in Spain.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 15 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 18 Apr 2011. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Spain. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Changes among genotypes in 24 h monitored Haloperidol and Risperidone pharmacokinetics (time frame: + 0.5h, +1h, +2h, +4h, +6h, +8h, +12h and +24h post-treatment). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01259973, which also lists 10 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Apr 2011.