Lopinavir/r/ Lamivudine/ Abacavir as an Easy to Use Paediatric Formulation

Overview

A phase I/II, open label, randomized crossover pharmacokinetic, safety and acceptability study of the Abacavir/Lamivudine/ Lopinavir/Ritonavir (30/15/ 40/10mg ;4-in-1) Fixed-Dose Combination vs. Lopinavir/Ritonavir (40/10mg pellets) plus dual Abacavir/Lamivudine (60/30mg tablets) in HIV infected Children.

The study is intended to support the adoption of the 4-in-1 by healthcare providers and will provide data that may support its registration in certain countries. The study will be carried out in HIV-infected children in Uganda weighing 3 to 25 kg (inclusive) and unable to swallow tablets and will provide supportive clinical data on the pharmacokinetics, safety, tolerability and acceptability of the 4-in-1.

Full Title of Study: “Pharmacokinetic, Safety and Acceptability Study of the Abacavir/Lamivudine/Lopinavir/Ritonavir/-30/15/ 40/10mg vs. Lopinavir/Ritonavir 40/10mg Pellets Plus Dual Abacavir/Lamivudine-60/30mg Tablets in HIV Infected Children”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Crossover Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: November 2019

Detailed Description

The primary objective is to estimate the population average exposure to LPV, ABC and 3TC provided by the 4-in-1 formulation in HIV-infected children dosed per WHO weight bands.

The secondary objectives:

- To determine the proportion of children overall, and within each weight band, with a lopinavir C12 <1.0 mg/L while receiving the 4-in-1 formulation

- To evaluate and compare the safety and tolerability of the 4-in-1 formulation versus a reference treatment regimen.

- To compare the bioavailability of LPV, ABC and 3TC in the 4-in-1 formulation versus a reference treatment regimen.

- To assess post exposure CD4 and viral load

- To assess the factors that contribute to acceptability of the new 4-in-1 formulation.

Interventions

  • Drug: ABC/3TC/LPV/r granules (30/15/40/10 mgs)
    • This is a fixed dose combination. Each capsule contains Lopinavir (40mg), Ritonavir (10mg), Abacavir (30mg) and Lamivudine (15mg) in granules formulation. Dosage according to patient’s weight: Between 3 and 5.9kg: 2 capsules twice a day Between 6 and 9.9kg: 3 capsules twice a day Between 10 and 13.9kg: 4 capsules twice a day Between 14 and 19.9kg: 5 capsules twice a day Between 20 and 24.9kg: 6 capsules twice a day
  • Drug: LPV/r Pellets (40/10mgs) plus ABC/3TC (60/30mgs)
    • Lopinavir/Ritonavir (40/10mg pellets) plus dual Abacavir/Lamivudine (60/30mg dispersible tablets) Dosage according to patient’s weight: LPV/r Pellets: Between 3 and 5.9kg: 2 capsules twice a day Between 6 and 9.9kg: 3 capsules twice a day Between 10 and 13.9kg: 4 capsules twice a day Between 14 and 19.9kg: 5 capsules twice a day Between 20 and 24.9kg: 6 capsules twice a day ABC/3TC: Between 3 and 5.9kg: 1 tablet twice a day Between 6 and 9.9kg: 1.5 tablets twice a day Between 10 and 13.9kg: 2 tablets twice a day Between 14 and 19.9kg: 2.5 tablets twice a day Between 20 and 24.9kg: 3 tablets twice a day

Arms, Groups and Cohorts

  • Experimental: 4in1 granules
    • Abacavir/Lamivudine/ Lopinavir/Ritonavir (30/15/ 40/10mg ;4-in-1) Fixed-Dose Combination in granules formulation administered twice daily for at least 3 weeks, Followed by Lopinavir/Ritonavir (40/10mg pellets) plus dual Abacavir/Lamivudine (60/30mg dispersible tablets) administered twice daily for at least 3 weeks.
  • Experimental: LPV/r Pellets Plus ABC/3TC
    • Lopinavir/Ritonavir (40/10mg pellets) plus dual Abacavir/Lamivudine (60/30mg dispersible tablets) administered twice daily for at least 3 weeks. Followed by Abacavir/Lamivudine/ Lopinavir/Ritonavir (30/15/ 40/10mg ;4-in-1) Fixed-Dose Combination in granules formulation administered twice daily for at least 3 weeks

Clinical Trial Outcome Measures

Primary Measures

  • 0 -12 hours Area under the curve plasma concentration versus time for LPV, ABC and 3TC in the 4-in- formulation
    • Time Frame: 0-12 hours
    • 0 -12 hours Area under the curve plasma concentration versus time for LPV, ABC and 3TC in the 4-in- formulation

Secondary Measures

  • Plasma concentration at 12 hours for LPV in the 4in1 formulation
    • Time Frame: 12 hours
    • Plasma concentration at 12 hours for LPV in the 4in1 formulation
  • Peak plasma concentration (Cmax) of LPV, ABC and 3TC with the 4-in-1 formulation.
    • Time Frame: 3-5 weeks
    • Plasma concentration maximum of LPV, ABC and 3TC with the 4-in-1 formulation.
  • Concentration time maximum for LPV, ABC and 3TC with the 4-in-1 formulation.
    • Time Frame: 3-5 weeks
    • Concentration time maximum for LPV, ABC and 3TC with the 4-in-1 formulation.
  • Clearance function for LPV, ABC and 3TC with the 4-in-1 formulation.
    • Time Frame: 3-5 weeks
    • Clearance function for LPV, ABC and 3TC with the 4-in-1 formulation.
  • Geometric mean ratio (GMR) of steady state LPV, ABC and 3TC versus time (0-12) in the 4-in-1 formulation versus the reference treatment regimen
    • Time Frame: 0 – 12 hours
    • Geometric mean ratio (GMR) of steady state LPV, ABC and 3TC versus time (0-12) in the 4-in-1 formulation versus the reference treatment regimen.
  • Area under curve plasma concentration versus time (0-12) in the 4-in-1 formulation versus the reference treatment regimen.
    • Time Frame: 0 – 12 hours
    • Area under curve plasma concentration versus time (0-12) in the 4-in-1 formulation versus the reference treatment regimen.
  • Geometric mean ratio (GMR) of steady state LPV, ABC and 3TC in the 4-in-1 formulation versus the reference treatment regimen.
    • Time Frame: 0 – 12 hours
    • Geometric mean ratio (GMR) of steady state LPV, ABC and 3TC in the 4-in-1 formulation versus the reference treatment regimen.
  • Peak plasma concentration in the 4-in-1 formulation versus the reference treatment regimen.
    • Time Frame: 3-5 weeks
    • Peak plasma concentration in the 4-in-1 formulation versus the reference treatment regimen.
  • Safety: A description of the proportion of children experiencing an Adverse event or Serious Adverse event binomial distribution compared between the two formulations.
    • Time Frame: 6-8 weeks
    • Safety: A description of the proportion of children experiencing an Adverse event or Serious Adverse event binomial distribution compared between the two formulations.
  • Safety: Summary of the number and percent of subjects with documented Grade 3 or higher adverse events; each summary will be conducted overall and by formulation
    • Time Frame: 6-8 weeks
    • Safety: Summary of the number and percent of subjects with documented Grade 3 or higher adverse events; each summary will be conducted overall and by formulation
  • Proportion of children with viral load <1000 copies/ml
    • Time Frame: 6-8 weeks
    • Comparison of proportion of children with viral load less than 1000 copies/ml at baseline and at end of the study.
  • Changes in CD4 counts compared to baseline
    • Time Frame: 6-8 week
    • Changes in CD4 counts compared to baseline
  • Changes in CD4 percentage compared to baseline
    • Time Frame: 6-8 weeks
    • Changes in CD4 percentage compared to baseline
  • Acceptability: Description of factors that affect acceptability of the 4 in1 formulation
    • Time Frame: 6-8 weeks
    • Description of factors that affect acceptability of the 4in1 formulation as reported by the caregivers

Participating in This Clinical Trial

Inclusion Criteria

  • Children > 4 weeks old and weighing ≥3 and <25 kg at the time of enrolment
  • Past or current documentation of a confirmed diagnosis of HIV infection defined as two positive assays from two different samples. The two results may be in any combination of the following:
  • At any age: HIV-1 DNA PCR positive
  • Documented past HIV-1 RNA viral load > 1,000 copies/mL plasma
  • At any age >18 months of age: HIV-1 antibody reactive on two different rapid tests based on national testing algorithm
  • ARV treatment eligible children with LPV-based treatment indication* as defined by country-specific guidelines or the WHO paediatric treatment guidelines and confirmed by the investigator
  • HIV RNA viral load <1000 copies/mL (suppressed) at the screening visit*
  • Inability to swallow LPV/r tablets
  • Parent or guardian able and willing to provide written informed consent.
  • For lowest weight band (≥3 and ≤ 5.9kgs) ONLY: under treatment for at least 3 weeks but not more than 12 weeks.
  • Does not apply to the youngest children (≥3 and ≤ 5.9kgs)

Exclusion Criteria

  • Planned or concurrent use of NNRTIs, integrase inhibitors, entry inhibitors, or Protease Inhibitors (PIs) other than LPV/r.
  • Treatment failure with proven resistances to PIs.
  • Contraindication to use of PIs
  • Clinical condition requiring the use of a prohibited medication (see section 7.6) in association with LPV/r, ABC/3TC (Refer to section 7.2- 7.3 of the IB)
  • Pulmonary Tuberculosis and any clinically significant disease or finding during screening that, in the investigator's opinion, would compromise participation in this study.
  • Treatment with experimental drugs (except for LPV/r Pellets) for any indication within 30 days prior to study entry
  • Anticipated transfer of care to a non-participating health facility during the study period

Gender Eligibility: All

Minimum Age: N/A

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Drugs for Neglected Diseases
  • Collaborator
    • UNITAID
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Isabelle Andrieux-Meyer, MD, Study Director, Drugs for neglected Diseases initiative
  • Overall Contact(s)
    • Isabelle Andrieux-Meyer, MD, +41 22 906 92 68, iandrieux-meyer@dndi.org

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