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Study of Excretion Balance and Pharmacokinetics of [14C]-Sodium Valproate (3.7 MBq) in Healthy Postmenopausal or Permanently Sterile Female Subjects

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03681158
Recruitment Status : Completed
First Posted : September 21, 2018
Last Update Posted : May 23, 2019
Sponsor:
Information provided by (Responsible Party):
Sanofi

Tracking Information
First Submitted Date  ICMJE September 14, 2018
First Posted Date  ICMJE September 21, 2018
Last Update Posted Date May 23, 2019
Actual Study Start Date  ICMJE October 5, 2018
Actual Primary Completion Date April 11, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 20, 2018)
  • Percentage of radioactive dose excreted in urine and feces [ Time Frame: Day 1 to Day 43 ]
    Fractional and cumulative percentage of radioactive dose excreted in urine and feces
  • Assessment of key metabolite(s) of sodium valproate [ Time Frame: Day 1 to Day 43 ]
    key metabolite(s) of sodium valproate will be assessed in plasma, urine and feces.
  • Assessment of PK parameters: Cmax [ Time Frame: Day 1 to 8, Day 12 to Day 15, Day 22, Day 29, Day 36, Day 43 ]
    Maximum plasma or blood concentration observed
  • Assessment of PK parameters: tmax [ Time Frame: Day 1 to 8, Day 12 to Day 15, Day 22, Day 29, Day 36, Day 43 ]
    Time to reach Cmax (tmax)
  • Assessment of PK parameters: AUClast [ Time Frame: Day 1 to 8, Day 12 to Day 15, Day 22, Day 29, Day 36, Day 43 ]
    Area under the plasma concentration versus time curve calculated from time zero to the real time, tlast (time corresponding to the last concentration above the limit of quantification, Clast (AUClast)
  • Assessment of PK parameters: AUC [ Time Frame: Day 1 to 8, Day 12 to Day 15, Day 22, Day 29, Day 36, Day 43 ]
    Area under the plasma concentration versus time curve extrapolated to infinity (AUC)
  • Assessment of PK parameters: t1/2z [ Time Frame: Day 1 to 8, Day 12 to Day 15, Day 22, Day 29, Day 36, Day 43 ]
    Terminal half-life associated with the terminal slope (λz) (t1/2z) in plasma, blood radioactivity and plasma VPA
  • Assessment of PK parameters: B/P (blood/plasma radioactivity ratio) [ Time Frame: Day 1 to 8, Day 12 to Day 15, Day 22, Day 29, Day 36, Day 43 ]
    Blood to plasma radioactivity ratio calculated at each time point
  • Assessment of PK parameters: RCmax (VPA to radioactivity ratio for plasma Cmax) [ Time Frame: Day 1 to 8, Day 12 to Day 15, Day 22, Day 29, Day 36, Day 43 ]
    RCmax is calculated as Cmax(VPA)/Cmax (radioactivity)
  • Assessment of PK parameters: RAUC (VPA to radioactivity ratio for plasma AUC) [ Time Frame: Day 1 to 8, Day 12 to Day 15, Day 22, Day 29, Day 36, Day 43 ]
    RAUC is calculated as AUC(VPA)/AUC (radioactivity)
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03681158 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: September 20, 2018)
Safety- Adverse Events [ Time Frame: From day -1 to 43 ]
Adverse events, spontaneously reported by the subject or observed by the Investigator from day -1 to day 43
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of Excretion Balance and Pharmacokinetics of [14C]-Sodium Valproate (3.7 MBq) in Healthy Postmenopausal or Permanently Sterile Female Subjects
Official Title  ICMJE An Open-label Study of Excretion Balance and Pharmacokinetics Following a Single Oral Dose of [14C]-Sodium Valproate (3.7 MBq) in Healthy Postmenopausal or Permanently Sterile Female Subjects
Brief Summary

Primary Objectives:

  • To determine the excretion balance and systemic exposure of radioactivity after oral administration of [14C]-sodium valproate (VPA) .
  • To determine the pharmacokinetics of sodium VPA and metabolite(s) and its contribution to the overall exposure of radioactivity.
  • To collect samples in order to determine the metabolic pathways of sodium VPA and identify the chemical structures and main excretion route of the main metabolites.

Secondary Objective:

To assess the clinical and biological tolerability of oral solution of sodium VPA.

Detailed Description Total study duration is 3 to 10 weeks, including a screening period of 8 to 28 days, treatment period of up to 15 days and a follow-up and end of study of up to 4 weeks.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Epilepsy
Intervention  ICMJE Drug: sodium valproate
Pharmaceutical form:Powder for oral solution reconstituted with water Route of administration: Oral
Other Name: LA40220
Study Arms  ICMJE Experimental: sodium valproate
Single oral dose of sodium valproate containing [14C]-sodium VPA
Intervention: Drug: sodium valproate
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 21, 2019)
5
Original Estimated Enrollment  ICMJE
 (submitted: September 20, 2018)
6
Actual Study Completion Date  ICMJE April 11, 2019
Actual Primary Completion Date April 11, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion criteria :

  • Female subjects, between 30 and 60 years of age, inclusive.
  • Body weight between 40.0 and 90.0 kg, inclusive, body mass index between 18.0 and 30.0 kg/m2, inclusive.
  • Certified as healthy by a comprehensive clinical assessment (detailed medical history and complete physical examination).
  • Normal vital signs after 10 minutes resting in supine position: 95 mmHg < systolic blood pressure (SBP) <140 mmHg or, for subjects over 45 years of age, <150 mmHg, 45 mmHg < diastolic blood pressure (DBP) <90 mmHg, 40 bpm < heart rate (HR) <100 bpm
  • Standard 12-lead electrocardiogram (ECG) parameters after 10 minutes resting in supine position in the following ranges; 120 ms<PR<220 ms, QRS<120 ms, QTc≤450 ms and normal ECG tracing unless the Investigator considers an ECG tracing abnormality to be not clinically relevant, or for subjects over 45 years of age, standard 12-lead ECG without clinically significant abnormality, in the judgment of the Investigator, with QTc≤470 ms.
  • Laboratory parameters within the normal range (or defined screening threshold for the Investigator site), unless the Investigator considers an abnormality to be clinically irrelevant for healthy subjects; however, serum creatinine, alkaline phosphatase, hepatic enzymes (aspartate aminotransferase, alanine aminotransferase), and total bilirubin (unless the subject has documented Gilbert syndrome) should not exceed the upper laboratory norm.
  • Surgically and permanently sterile (hysterectomy, bilateral salpingectomy or bilateral salpingo-oophorectomy) at least 3 months earlier or postmenopausal. Menopause is defined as being amenorrheic for at least 2 years with plasma FSH level > 30 UI/L. No additional contraception is required.
  • Having given written informed consent prior to undertaking any study-related procedure.
  • Covered by a health insurance system where applicable, and/or in compliance with the recommendations of the national laws in force relating to biomedical research.
  • Not under any administrative or legal supervision.
  • Normal renal function as expressed by a creatinine clearance > 80 mL/min as calculated by the Cockroft and Gault formula

Exclusion criteria:

  • Any subject with specific dietary habits, such as vegan.
  • Any subject with irregular bowel habits (more than 3 bowel movements/day or less than 1 every 2 days).
  • Any subject undergoing dental care or presenting with dental caries.
  • Any subject who is occupationally exposed to radiation as defined in the Ionising Radiations Regulations 2017.
  • Participation in a trial with 14C-radiolabelled medication in the 12 months preceding the study.
  • Radiation exposure, including that from the present study and radiopharmaceuticals or radionuclides in therapeutic or diagnostic procedures, but excluding background radiation, exceeding 5 mSv in the last 12 months or 10 mSv in the last 5 years.
  • Poor metabolizer status for CYP2C9, CYP2C19, CYP2D6 (by genotyping).
  • Any consumption of citrus (grapefruit, orange, etc) or their juices within 5 days before inclusion.
  • Any contra-indications to sodium VPA according to the applicable labeling (including personal or family history of severe hepatic dysfunction, urea cycle disorders, porphyria, hypersensitivity to valproate, active liver disease, pregnancy, child bearing potential) and patients known to have mitochondrial disorders caused by mutations in the nuclear gene encoding mitochondrial enzyme polymerase γ (POLG, e.g. Alpers-Huttenlocher Syndrome).

The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 30 Years to 60 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03681158
Other Study ID Numbers  ICMJE BEX15316
2017-004987-36 ( EudraCT Number )
U1111-1205-1651 ( Other Identifier: UTN )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://www.clinicalstudydatarequest.com/
Responsible Party Sanofi
Study Sponsor  ICMJE Sanofi
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Clinical Sciences & Operations Sanofi
PRS Account Sanofi
Verification Date May 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP