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The Effect of Phenytoin on the Pharmacokinetics of Nevirapine and the Development of Nevirapine Resistance (VITA 2)

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ClinicalTrials.gov Identifier: NCT01187719
Recruitment Status : Completed
First Posted : August 24, 2010
Last Update Posted : December 1, 2020
Sponsor:
Information provided by (Responsible Party):
Radboud University

Tracking Information
First Submitted Date  ICMJE August 23, 2010
First Posted Date  ICMJE August 24, 2010
Last Update Posted Date December 1, 2020
Study Start Date  ICMJE May 2010
Actual Primary Completion Date June 2012   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 23, 2010)
half-life time nevirapine [ Time Frame: untill two weeks after NVP dosing ]
blood samples will be taken <30 min after delivery, 24 hours after delivery, at day 3, at day 5, at day 7 and at day 14
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 23, 2010)
  • NVP resistance [ Time Frame: week 4 / week 6 after delivery ]
    resistance testing at week 4 or week 6 after delivery (and NVP dosing).
  • safety of co-administration phenytoin and NVP [ Time Frame: entire trial ]
    Adverse events will be collected during the entire trial (for both mother and child).
  • HIV status of the newborn [ Time Frame: week 6 after birth ]
    HIV status of the newborn will be assessed at week 6 after birth.
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 The Effect of Phenytoin on the Pharmacokinetics of Nevirapine and the Development of Nevirapine Resistance
Official Title  ICMJE The Effect of Phenytoin on the Pharmacokinetics of Nevirapine and the Development of Nevirapine Resistance After a Single Dose Nevirapine (VIramune®), Which is Part of ARV Prophylaxis for PMTCT in Moshi, TAnzania, and in Lusaka, Zambia (VITA2 Trial)
Brief Summary

The primary objective of this two-phase trial is as follows:

  • To determine the elimination half-life of NVP in HIV positive pregnant women receiving it as a single dose in labour in addition to the ZDV and 3TC with or without seven days phenytoin (pilot PK phase)
  • To determine NVP resistance in HIV positive pregnant women receiving it as a single dose in labour in addition to ZDV and 3TC with or without seven days phenytoin (main trial phase)

The secondary objectives of this two-phase trial are as follows:

  • To determine the safety of single dose nevirapine with seven days phenytoin as a part of ARV prophylaxis for PMTCT vs. single dose of nevirapine without phenytoin as a part of ARV prophylaxis for PMTCT
  • To determine the HIV status of the infant
  • To determine the safety of the ARV prophylaxis for PMTCT with seven days of phenytoin on the newborn

Hypothesis: phenytoin reduces the elimination half life of SD NVP and thereby decreases development of resistance to NVP in HIV positive pregnant Tanzanian and Zambian women.

Detailed Description

This trial (VITA2) will be done with phenytoin as enzyme inducer to decrease the elimination half-life of NVP as it has also shown a significant difference in the elimination half-life of NVP in the ENVI study and side effects were also transient and mild. The guidelines for ARV prophylaxis for PMTCT has been changed to a more complex regimen. Therefore addition of phenytoin OD for 7 days after delivery will not complicate the regimen for the mother.

Tanzania and Zambia are among the countries in sub-Saharan Africa most affected by the HIV pandemic. In 2008, an estimated 85,000 children were living with HIV in Zambia and out of the 89,000 children born to HIV infected women, 28,000 are infected annually. In Tanzania, 140,000 children were living with HIV in 2007. Both countries use NVP alone or in combination with other drugs as ARV prophylaxis for PMTCT. Little data are available on the extent of NVP resistance in the Tanzanian, Zambian PMTCT setting. Moreover, there is no data available on the follow-up of mother-infant pair with particular focus on resistance to NVP and the infants HIV status. No studies have explored possibilities of reducing NVP resistance by use of an enzyme inducer.

This study seeks to the effect of phenytoin on the pharmacokinetics of NVP and the development of NVP resistance on SD NVP as part of the ARV prophylaxis for PMTCT. This intervention will be part of the VITA2 trial to test the hypothesis that phenytoin reduces the elimination half life of SD NVP and thereby decreases development of resistance to NVP in HIV positive pregnant Tanzanian and Zambian women.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Condition  ICMJE
  • HIV-infection
  • Pregnancy
  • Mother to Child Transmission
Intervention  ICMJE Drug: phenytoin
phenytoin 184 mg (2 tablets of 92mg) OD at onset of labour and continue for seven days
Study Arms  ICMJE
  • No Intervention: Control
    ARV prophylaxis for PMTCT follows national guidelines.
  • Experimental: phenytoin interaction
    ARV prophylaxis for PMTCT follows national guidelines + start phenytoin 184 mg (2 tablets of 92mg) OD at onset of labour and continue for seven days
    Intervention: Drug: phenytoin
Publications * Fillekes Q, Muro EP, Chunda C, Aitken S, Kisanga ER, Kankasa C, Thomason MJ, Gibb DM, Walker AS, Burger DM. Effect of 7 days of phenytoin on the pharmacokinetics of and the development of resistance to single-dose nevirapine for perinatal HIV prevention: a randomized pilot trial. J Antimicrob Chemother. 2013 Nov;68(11):2609-15. doi: 10.1093/jac/dkt246. Epub 2013 Jul 17.

*   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: June 15, 2011)
66
Original Estimated Enrollment  ICMJE
 (submitted: August 23, 2010)
200
Actual Study Completion Date  ICMJE September 2012
Actual Primary Completion Date June 2012   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • HIV-infected as documented by positive HIV antibody test
  • Antiretroviral naïve
  • Starting ARV prophylaxis from 28th weeks of gestation or at least 4 weeks before delivery
  • Not intending to relocate out of the area for the duration of study participation
  • Willingness of subject to adhere to follow up schedule (note: this is more intensive for the pilot PK phase)
  • Ability and willingness of subject to give written consent
  • Pregnant women aged 18 years and above
  • Willing and able to regularly attend the antenatal clinic

Exclusion Criteria:

  • Serious illness that requires systemic treatment or hospitalization
  • Use of concomitant medication, which interferes with the ARV prophylaxis for PMTCT or phenytoin
  • Any condition that in the opinion of the investigator would compromise the subjects' ability to participate in the study
  • Previously treated for HIV infection with antiretroviral agents, including ARV prophylaxis for PMTCT
  • Inability to understand the nature and extent of the trial and the procedures required
  • CD4 count <350 cells/µl because such a patient is eligible for HAART
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Tanzania,   Zambia
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01187719
Other Study ID Numbers  ICMJE UMCN-AKF 09.02
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Radboud University
Study Sponsor  ICMJE Radboud University
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Elton Kisanga, PharmD, PhD Kilimanjaro Christian Medical Centre
PRS Account Radboud University
Verification Date November 2020

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