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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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HIV

Intervention / Treatment
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* Drug: ABC/3TC/LPV/r granules (30/15/40/10 mgs)
* Drug: LPV/r Pellets (40/10mgs) plus ABC/3TC (60/30mgs)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 4 Weeks

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 4in1 granules<br>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)<br>* 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<br>* Other names: 4in1 Granules;Drug: LPV/r Pellets (40/10mgs) plus ABC/3TC (60/30mgs)<br>* 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<br>* Other names: L PV/r Pellets Plus ABC/3TC tablets;|
| Experimental: LPV/r Pellets Plus ABC/3TC<br>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)<br>* 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<br>* Other names: 4in1 Granules;Drug: LPV/r Pellets (40/10mgs) plus ABC/3TC (60/30mgs)<br>* 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<br>* Other names: L PV/r Pellets Plus ABC/3TC tablets;|

What is the study measuring?
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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 |