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Variability of Sulfotransferase 1A1 Activity in Humans: an Approach to Improve Predictive Drug Response - Part I: Analysis of Intraindividual Variation in Healthy Adults

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ClinicalTrials.gov Identifier: NCT03182595
Recruitment Status : Unknown
Verified June 2017 by Hospital da Luz, Portugal.
Recruitment status was:  Recruiting
First Posted : June 9, 2017
Last Update Posted : June 9, 2017
Sponsor:
Collaborator:
Universidade Nova de Lisboa
Information provided by (Responsible Party):
Hospital da Luz, Portugal

Brief Summary:
An open‐label, single centre, nonrandomized clinical study in healthy volunteers, with intervention over a 13--‐week period. After written informed consent, subjects will undergo screening evaluations (Visit 1). One week after visit 1, subjects who meet the selection criteria will enter a run--‐in period of 8 weeks where participants will receive paracetamol 1g tablet and collect a blood sample at monthly intervals (visits 2, 3 and 4). A final visit for safety assessment will take place at week 13 (visit 5). Blood samples will be used to quantify P, PG e PS.

Condition or disease Intervention/treatment Phase
Healthy Volunteers Drug: Paracetamol Phase 1

Detailed Description:
To be able to predict efficacy and adverse reactions involving compounds metabolized by sulfonation, the investigators need more information on SULTs. Studies of in vivo sulfonation in humans are lacking, although they are of key importance in assessing the functional consequences of individual variation. In our current study, the investigators will start by developing an HPLC method of quantifying SULT1A1 activity using paracetamol as probe substrate and studying intraindividual variation in healthy adults. Advantages of using paracetamol as a probe substrate for in vivo phenotyping of SULT1A1 include: wide safety margin for in vivo use, easy and ready administration of the drug, significant metabolism by the enzyme of interest, short half--‐life, linear pharmacokinetics over a wide concentration range and a limited number of metabolites, quantifiable in plasma.15,24 In a subsequent study, the investigators plan to study interindividual variation in a larger sample, including subjects with chronic disease and on medication.The investigators expect to provide a valuable new tool to explore the clinical significance of variation of SULT1A1 activity, the most important SULT on drug metabolism.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Variability of Sulfotransferase 1A1 Activity in Humans: an Approach to Improve Predictive Drug Response - Part I: Analysis of Intraindividual Variation in Healthy Adults
Actual Study Start Date : March 17, 2017
Estimated Primary Completion Date : December 2017
Estimated Study Completion Date : January 2018

Arm Intervention/treatment
Experimental: open--‐label
An open--‐label, single centre, nonrandomized clinical study in healthy volunteers, with intervention over a 13--‐week period.
Drug: Paracetamol
Volunteers will be screened at visit 1, and if they meet the inclusion/exclusion criteria they will receive the intervention at visit 2. At visit 2, complying subjects will receive a tablet containing 1 gram of paracetamol and have a blood sample collected 2 hours after administration; these procedures will be repeated on 2 more occasions (visits 3 and 4). The subjects will come for 5 visits during the study. Visit 1 and 2 must occur within 7 days of each other, visits 2, 3 and 4 will be four weeks (± 3 days) apart and visit 5 scheduled four weeks (± 3 days) after visit 4.




Primary Outcome Measures :
  1. - Coefficient of variation of paracetamol sulfonation index (PSI), a ratio between the measured plasma concentrations of paracetamol sulfate (PS) and PS+ paracetamol glucoronide (PG) + paracetamol (P) [ Time Frame: 9 months ]

Secondary Outcome Measures :
  1. Reproductibility, sensitivity and accuracy of the HPLC method (human samples will be used to validate the method); [ Time Frame: 9 months ]
  2. Relationships between PSI and subject characteristics (gender, age, genotype, smoking status, caffeine consumption, alcohol consumption, oral contraceptive use); [ Time Frame: 9 months ]
  3. Relationship between SULTA1 expression and predose and postdose metabolic profiles; [ Time Frame: 9 months ]
  4. Association between SULT1A1 genotype and SULT1A1 expression (optional); [ Time Frame: 9 months ]
  5. Association between PSI and SULT1A1 genotype (optional). [ Time Frame: 9 months ]


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Healthy males and females, over 18 years of age,
  • Informed of the nature of the study and giving written informed consent,
  • Report no significant diseases during screening,
  • Have normal CBC, renal function and liver enzymology,
  • Have no contraindication for paracetamol,
  • Be on no regular medical treatment, except for contraceptives,
  • Be able to communicate effectively with study personnel.

Exclusion Criteria:

  • Hypersensitivity or idiosyncratic reaction to paracetamol,
  • Intake of any medication, except for contraceptives, within 14 days before start of the study,
  • Pregnancy or breastfeeding,
  • BMI <18 kg/m2,
  • Participation in a clinical study of any investigational product 1 month prior to visit 1 or during the study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03182595


Contacts
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Contact: Natália Marto, MD +351217104400 nfmarto@hospitaldaluz.pt
Contact: Rita Eça +351217104400 ext 14075 rheca@hospitaldaluz.pt

Locations
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Portugal
Hospital da Luz Recruiting
Lisboa, Portugal, 1500-650
Contact: Rita Eca    +351926609649 ext 14075    rheca@hospitaldaluz.pt   
Sponsors and Collaborators
Hospital da Luz, Portugal
Universidade Nova de Lisboa
Investigators
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Principal Investigator: Natália Marto, MD Hospital da Luz

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Responsible Party: Hospital da Luz, Portugal
ClinicalTrials.gov Identifier: NCT03182595     History of Changes
Other Study ID Numbers: HLUZ_001_2016
First Posted: June 9, 2017    Key Record Dates
Last Update Posted: June 9, 2017
Last Verified: June 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:
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Acetaminophen
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Antipyretics