IMPAACT P1092: Steady State PK in Malnourished HIV Infected Children

NCT01818258 | Completed Phase 4 Results DMC

• 3 other identifiers: IMPAACT P1092U01AI06863211689
• Study Type: interventional
• Target: 52
• Locations: 4 countries
• Sites: 5

Brief Summary

Children living with HIV from sub-Saharan Africa often present with severe malnutrition. In severe malnutrition, metabolic and/or gut structural derangement may lead to inadequate antiretroviral (ARV) absorption and/or erratic drug levels. The greater surface area to weight ratio in severely malnourished children could also place them at higher risk of under dosing compared to children with mild to moderate malnutrition. However, limited data are available on the pharmacokinetics of ARVs in severely malnourished children. This study addressed this critical gap in knowledge by evaluating the PK of zidovudine (ZDV), lamivudine (3TC), and lopinavir/ritonavir (LPV/r) in severely malnourished children living with HIV, compared to children with normal nutrition to mild malnutrition living with HIV.

Conditions

HIV Positive; Malnourished

Keywords

HIV; Children; HAART; Malnourished

Outcome Measures

Primary Outcomes (10)

• Grade 3 or Higher Adverse Events Through 24 Weeks

  Number (percent) of participants with at least one grade 3 or higher adverse event (AE) regardless of the relationship to study drugs.

  From week 0 to week 24

• Grade 3 or Higher Adverse Events Related to Study Drugs Through Week 24

  Number (percent) of participants with at least one Grade 3 or higher adverse event related to study drugs

  From week 0 to week 24

• Steady-state Lopinavir Area Under the Curve

  Steady-state area under the curve (AUC) for Lopinavir (LPV)

  0, 1, 2, 4, 8, and 12 hours post-dose on 1, 12, and 24 weeks following study entry

• Plasma Clearance of Lopinavir

  Steady-state plasma clearance (CL/F) of LPV

  0, 1, 2, 4, 8, and 12 hours post-dose on 1, 12, and 24 weeks following study entry

• Steady-state Ritonavir Area Under the Curve

  Steady-state area under the curve (AUC) for Ritonavir (RTV)

  0, 1, 2, 4, 8, and 12 hours post-dose on 1, 12, and 24 weeks following study entry

• Plasma Clearance of Ritonavir

  Steady-state plasma clearance (CL/F) of RTV

  0, 1, 2, 4, 8, and 12 hours post-dose on 1, 12, and 24 weeks following study entry

• Steady-state Lamivudine Area Under the Curve

  Steady-state area under the curve (AUC) of Lamivudine (3TC)

  0, 1, 2, 4, 8, and 12 hours post-dose on 1, 12, and 24 weeks following study entry

• Plasma Clearance of Lamivudine

  Steady-state plasma clearance (CL/F) of Lamivudine (3TC)

  0, 1, 2, 4, 8, and 12 hours post-dose on 1, 12, and 24 weeks following study entry

• Steady-state Zidovudine Area Under the Curve

  Steady-state area under the curve (AUC) of zidovudine (ZDV)

  0, 1, 2, 4, 8, and 12 hours post-dose on 1, 12, and 24 weeks following study entry

• Plasma Clearance of Zidovudine

  Steady-state plasma clearance (CL/F) of Zidovudine (ZDV)

  0, 1, 2, 4, 8, and 12 hours post-dose on 1, 12, and 24 weeks following study entry

Secondary Outcomes (7)

• Minimum Trough Concentration (Ctrough) of Lopinavir

  Measured 0, 1, 2, 4, 8, and 12 hours post-dose on 1, 4, 8, 12, 16, 24, 36 and 48 weeks following study entry

• Free Fraction of LPV at Hour 2 Post Dose

  Weeks 1, 12 and 24

• Change in HIV Viral Load From Baseline

  Weeks 0, 12, 24, 36 and 48

• HIV Viral Load <400 Copies/mL

  Baseline and weeks 12, 24, and 48

• Change in CD4 Percent

  Weeks 0, 12, 24, 36 and 48

Study Arms (2)

Severe Malnutrition

ACTIVE COMPARATOR

ZDV+3TC+LPV/r Zidovudine (ZDV, Retrovir®) 10 mg/ml oral syrup administered twice daily at WHO weight band dose for 48 weeks; Lamivudine (Epivir®, 3TC) 10 mg/ml for oral solution administered twice daily at WHO weight band dose for 48 weeks; Lopinavir/ritonavir (Kaletra®, LPV/r) 80/20 mg/ml oral solution administered twice daily at the WHO weight band dose for 48 weeks

Drug: ZDV+3TC+LPV/r

Normal Nutrition/Mild Malnutrition

ACTIVE COMPARATOR

ZDV+3TC+LPV/r Zidovudine (ZDV, Retrovir®) 10 mg/ml oral syrup administered twice daily at WHO weight band dose for 48 weeks; Lamivudine (Epivir®, 3TC) 10 mg/ml for oral solution administered twice daily at WHO weight band dose for 48 weeks; Lopinavir/ritonavir (Kaletra®, LPV/r) 80/20 mg/ml oral solution administered twice daily at the WHO weight band dose for 48 weeks

Drug: ZDV+3TC+LPV/r

Interventions

ZDV+3TC+LPV/r DRUG

Also known as: Zidovudine, Retrovir, Lamivudine, Epivir, Lopinavir/ritonavir, Kaletra

Normal Nutrition/Mild Malnutrition; Severe Malnutrition

Eligibility Criteria

• Age: 6 Months - 36 Months
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Documentation of HIV-1 infection defined as positive results from two samples collected at different time points, using protocol-specified tests
• Meets WHO classification for severe malnutrition, normal nutrition status, or mild malnutrition
• Eligible for HAART defined by WHO 2013 pediatric guidelines
• Parent or legal guardian able and willing to provide signed informed consent, remain within the study area during the study period and agree to have subject followed at the clinical site
• Qualifying hematology and chemistry laboratory values obtained from specimens collected within the study-specific screening period
• For severely malnourished children: An inpatient in a nutrition rehabilitation unit. Clinical improvement after 10-18 days on nutrition rehabilitation defined as: Appetite returned and eating better - child shows interest in food even if does not complete amount given:
• No further weight loss
• Normalized sodium and potassium defined as severity grade 1 or lower
• No evidence of cardiac failure
• Loss of apathy and starting to play
• No hypothermia or pyrexia - temperature stable at \>35.0 to \<38.0° C (non-axillary) or \>34.4 to \<37.4° C (axillary)
• For children with normal - mild malnutrition, clinical stability will be indicated by:
• Good appetite
• Normalized sodium and potassium defined as severity grade 1 or lower
• No hypothermia or pyrexia - temperature stable at \>35.0 to \<38.0° C (non-axillary) or \>34.4 to \<37.4° C (axillary)

You may not qualify if:

• Edematous malnutrition at the time of study entry
• ≥ Grade 3 respiratory distress or presence of cardio respiratory compromise within 3 days prior to entry
• Chemotherapy for malignancy
• Acute infection for which the child has received appropriate antimicrobial treatment for \<5 days
• Tuberculosis disease
• Clinic hepatitis as evidenced by jaundice and hepatomegaly
• Taking any disallowed medications
• Any condition, situation, or clinical finding that in the opinion of the investigator would place the child at an unacceptable level of risk for injury, or render the child/caregiver(s) unable to meet the requirements of the study, interfere with study participation, or in the interpretation of study results.

Sponsors & Collaborators

• International Maternal Pediatric Adolescent AIDS Clinical Trials Group: lead
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator
• National Institute of Mental Health (NIMH): collaborator

Study Sites (5)

Blantyre CRS (30301)

Blantyre, Malawi

Location

Malawi CRS (12001)

Lilongwe, Malawi

Location

Kilimanjaro Christian Medical Centre (5118)

Moshi, Tanzania

Location

Makerere University-Johns Hopkins University (MUJHU) Research Collaboration (30293)

Kampala, Uganda

Location

Harare Family Care (31890)

Harare, Zimbabwe

Location

Related Publications (2)

• Owor M, Tierney C, Ziemba L, Browning R, Moye J, Graham B, Reding C, Costello D, Norman J, Wiesner L, Hughes E, Whalen ME, Purdue L, Mmbaga BT, Kamthunzi P, Kawalazira R, Nathoo K, Bradford S, Coletti A, Aweeka F, Musoke P. Pharmacokinetics and Safety of Zidovudine, Lamivudine, and Lopinavir/Ritonavir in HIV-infected Children With Severe Acute Malnutrition in Sub-Saharan Africa: IMPAACT Protocol P1092. Pediatr Infect Dis J. 2021 May 1;40(5):446-452. doi: 10.1097/INF.0000000000003055.

  PMID: 33464021 RESULT

• Bwakura-Dangarembizi M, Ziemba L, Tierney C, Reding C, Bone F, Bradford S, Costello D, Browning R, Moye J, Vhembo T, Ngocho JS, Mallewa M, Chinula L, Musoke P, Owor M. Micronutrients and nutritional status among children living with HIV with and without severe acute malnutrition: IMPAACT P1092. BMC Nutr. 2023 Nov 2;9(1):121. doi: 10.1186/s40795-023-00774-1.

  PMID: 37919816 DERIVED

Related Links

• Signs/symptoms, laboratory events, and diagnoses were graded using the Division of AIDS (DAIDS) Table for Grading Severity of Adult and Pediatric Adverse Events, Corrected Version 2.0, November 2014.
• Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual), Version 2.0, January 2010

MeSH Terms

Conditions

HIV Seropositivity; Malnutrition

Interventions

Zidovudine; Lamivudine; Lopinavir; lopinavir-ritonavir drug combination

Condition Hierarchy (Ancestors)

HIV Infections; Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Nutrition Disorders; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Thymidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Dideoxynucleosides; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Zalcitabine; Deoxycytidine; Cytidine; Pyrimidinones

Limitations and Caveats

Children with moderate malnutrition were not enrolled in the study by design

Results Point of Contact

• Title: IMPAACT Clinicaltrials.gov Coordinator
• Organization: Organization: Family Health International (FHI 360)

IMPAACT.ctgov@fstrf.org

(919) 405-1429

Study Officials

• Maxensia O Owor, MBChB, MMED, MPH

  International Maternal Pediatric Adolescent AIDS Clinical Trials Group

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 14, 2013
• First Posted: March 26, 2013
• Study Start: October 26, 2015
• Primary Completion: April 11, 2017
• Study Completion: September 29, 2017
• Last Updated: August 12, 2021
• Results First Posted: August 12, 2021

Record last verified: 2021-07

Data Sharing

• IPD Sharing: Will not share

Locations

MA (2); TA (1); UG (1); ZI (1)