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

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

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.

Study Overview

• Status: Unknown
• Conditions: HIV
• Intervention / Treatment: Drug: ABC/3TC/LPV/r granules (30/15/40/10 mgs); Drug: LPV/r Pellets (40/10mgs) plus ABC/3TC (60/30mgs)

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.

• Study Type: Interventional
• Enrollment (Anticipated): 50
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Uganda
  • Kampala, Uganda
    • Recruiting
    • Baylor College of Medicine Children's Foundation Uganda
    • Contact: Prof. Adeodata Kekitiinwa, MBChM, MMeD; Phone Number: +256772462686; Email: akekitiinwa@baylor-uganda.org
  • Kampala, Uganda
    • Recruiting
    • Joint Clinical Research Centre
    • Contact: Victor Musiime, MBChB,PhD; Phone Number: +256 417 723000; Email: vmusiime@jcrc.org.ug
  • Mbarara, Uganda
    • Recruiting
    • Epicentre Mbarara Research Centre
    • Contact: Prof. Juliet Mwanga, MBChB, MMED; Phone Number: +256 793328748; Email: juliet.mwanga@epicentre.msf.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 weeks and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.	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; Other Names: 4in1 Granules; 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; Other Names: L PV/r Pellets Plus ABC/3TC tablets
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	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; Other Names: 4in1 Granules; 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; Other Names: L PV/r Pellets Plus ABC/3TC tablets

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Drugs for Neglected Diseases
• Collaborators: Institute of Tropical Medicine, Belgium; UNITAID; AMS-PHPT Research Platform (Program for HIV Prevention and Treatment); Joint Clinical Research Centre- Kampala; Baylor College of Medicine Childrens Foundation, Uganda; Epcentre Centre Mbarara Research Centre
• Investigators: Study Director: Isabelle Andrieux-Meyer, MD, Drugs for Neglected Diseases initiative

Study record dates

Study Major Dates

• Study Start (Actual): June 4, 2019
• Primary Completion (Anticipated): November 1, 2019
• Study Completion (Anticipated): December 1, 2019

Study Registration Dates

• First Submitted: December 13, 2018
• First Submitted That Met QC Criteria: February 8, 2019
• First Posted (Actual): February 11, 2019

Study Record Updates

• Last Update Posted (Actual): June 7, 2019
• Last Update Submitted That Met QC Criteria: June 5, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Lamivudine
• Other Study ID Numbers: DNDi-4in1-01-PHIV

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• 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