Safety, Tolerance and Pharmacokinetics of Raltegravir-Containing Antiretroviral Therapy in Infants, Children Infected With HIV and TB

NCT01751568 | Completed Phase 1 Results DMC

• 3 other identifiers: P110111831IMPAACT P1101
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 4

Brief Summary

People who are infected with HIV and tuberculosis (TB) need to receive medications that treat both diseases safely and effectively. This study enrolled infants and children infected with HIV and TB and evaluated the safety and tolerance of an antiretroviral (ARV) treatment regimen for HIV that contains raltegravir when administered with a TB treatment regimen that includes rifampicin. Study researchers aimed to determine the most effective dose of raltegravir for infants and children when taken with rifampicin.

Conditions

HIV Infections; Tuberculosis

Outcome Measures

Primary Outcomes (6)

• Number of Participants Who Permanently Discontinued Treatment Due to Adverse Event(s) of Greater Than or Equal to Grade 3 Deemed at Least Possibly Related to Raltegravir

  Number (Frequency) of participants who permanently discontinued raltegravir study treatment due to an adverse event(s) of greater than or equal to Grade 3, deemed at least possibly related to raltergravir.

  Measured from the first dose of raltegravir through the participant's last study visit (median of 34 weeks)

• Number of Participants Who Experienced Death, Grade 4 Life-threatening Adverse Events Deemed at Least Possibly Related to Raltegravir

  Number (Frequency) of participants who experienced Death, Grade 4 life-threatening adverse events deemed at least possibly related to raltegravir

  Measured from the first dose of raltegravir through a participant's last study visit (median of 34 weeks)

• Number of Participants Who Experienced Grade 4 Non-life Threatening Adverse Event(s) Deemed as Probably or Definitely Related to Raltegravir

  Number (Frequency) of Participants who experienced Grade 4 non-life threatening adverse event(s) deemed as probably or definitely related to raltegravir

  Measured from the first dose of raltegravir through a participant's last study visit (median of 34 weeks)

• Number of Participants Who Experienced Adverse Event(s) of Greater Than or Equal to Grade 3 Deemed at Least Possibly Related to Raltegravir

  Number (Frequency) of Participants who experienced Adverse event(s) of greater than or equal to Grade 3 deemed at least possibly related to raltegravir

  Measured from the first dose of raltegravir through a participant's last study visit (median of 34 weeks)

• Pharmacokinetic (PK) Parameter: Area Under the Curve (AUC12h)

  Pharmacokinetic parameters were determined from plasma concentration-time profiles using noncompartmental methods (Phoenix WinNonlin 8.1, Certara, Princeton, New Jersey). AUC12h (area-under-the-curve from 0 to 12 hours) were determined using the linear-log trapezoidal rule. Geometric Means (GM) for AUC12h were calculated for each cohort.

  At the study visit between days 5 and 8 of raltegravir initiation; A (0.5) mL of blood sample was drawn at each time point: pre-dose (0), 0.5, 1, 2, 3, 4, 6, 8, and 12 hours post dosing.

• Pharmacokinetic (PK) Parameter: Concentration at 12h (C12)

  Pharmacokinetic parameters were determined from plasma concentration-time profiles using noncompartmental methods (Phoenix WinNonlin 8.1, Certara, Princeton, New Jersey). AUC12h (area-under-the-curve from 0 to 12 hours) were determined using the linear-log trapezoidal rule. Geometric Means (GM) for C12 were calculated for each cohort.

  At the study visit between days 5 and 8 of raltegravir initiation; A (0.5) mL of blood sample was drawn at each time point: pre-dose (0), 0.5, 1, 2, 3, 4, 6, 8, and 12 hours post dosing.

Secondary Outcomes (2)

• Number of Participants Who Failed to Respond Virologically at Week 8, Which Means Having HIV RNA (Copies/mL) Greater Than 400 Copies/mL AND Less Than 1-log10 Drop From Baseline

  Measured at Week 8

• Number of Participants Who Developed of New Opportunistic Infection(s) (OIs)

  Measured from the first dose of raltegravir through a participant's last study visit (median of 34 weeks)

Study Arms (3)

Cohort 1: ≥ 2 to < 6 years of age on TB treatment

EXPERIMENTAL

Participants in this cohort received chewable raltegravir tablets, starting dose of 12 mg/kg (up to a maximum of 800 mg) orally twice daily, in addition to two NRTIs to treat HIV as part of standard of care, and a rifampicin-containing regimen to treat TB. After a study visit at Day 5 to 8, a fourth ARV medication was added to the regimen.

Drug: Raltegravir

Cohort 2: ≥ 6 to < 12 years of age on TB treatment

EXPERIMENTAL

Participants in this cohort received chewable raltegravir tablets, starting dose of 12 mg/kg (up to a maximum of 800 mg) orally twice daily, in addition to two NRTIs to treat HIV as part of standard of care, and a rifampicin-containing regimen to treat TB. After a study visit at Day 5 to 8, a fourth ARV medication was added to the regimen.

Drug: Raltegravir

Cohort 3: : ≥ 4 weeks to < 2 years of age on TB treatment

EXPERIMENTAL

Participants in this cohort received chewable raltegravir tablets (as a dispersible tablet), starting dose of 12 mg/kg (up to a maximum of 800 mg) orally twice daily, in addition to two NRTIs to treat HIV as part of standard of care, and a rifampicin-containing regimen to treat TB. After a study visit at Day 5 to 8, a fourth ARV medication was added to the regimen.

Drug: Raltegravir

Interventions

Raltegravir DRUG

Chewable raltegravir tablets, initially dosed at 12 mg/kg (up to a maximum of 800 mg) orally twice daily.

Cohort 1: ≥ 2 to < 6 years of age on TB treatment; Cohort 2: ≥ 6 to < 12 years of age on TB treatment; Cohort 3: : ≥ 4 weeks to < 2 years of age on TB treatment

Eligibility Criteria

• Age: 4 Weeks - 11 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Weight greater than or equal to 3.5 kg at entry
• Confirmation of HIV-1 infection was defined as positive results from two samples collected at different time points. All samples tested must be whole blood, serum, or plasma. For studies conducted under an Investigational New Drug (IND), all test methods should be Food and Drug Administration (FDA)-approved if available. If FDA-approved methods are not available, test methods should be verified according to good clinical laboratory practice (GCLP) and approved by the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Laboratory Center. More information on this criterion can be found in the protocol.
• ARV treatment naïve or did not received ARVs for at least 30 days prior to entry. Note: Participants with prior exposure to ARVs for prevention of mother-to-child transmission (PMTCT) or treatment - regardless of duration - were eligible provided the participant did not received ARVs for at least 30 days prior to entry. The reasons for interruption could include drug toxicity, poor adherence, or treatment failure that preceded enrollment and was not imposed by study staff. ARVs should not be withheld for the purposes of enrollment into the study and against the participant's best interest.
• ARV treatment eligible as defined by:
• Country-specific guidelines OR
• World Health Organization (WHO) pediatric treatment algorithm (http://apps.who.int/iris/bitstream/10665/208825/1/9789241549684\_eng.pdf?ua=1)
• Diagnosis of pulmonary TB or TB adenitis. More information on this criterion can be found in the protocol.
• Participant initiated at least a 2-drug TB regimen containing rifampicin, and had tolerated at least 1 week of the TB drug regimen prior to initiation of raltegravir. Note: TB treatment was allowed to be started after being diagnosed by the site investigator. Treatment regimens included isoniazid, pyrazinamide, ethambutol and streptomycin in addition to rifampicin. ART ideally started within 2 weeks of starting TB treatment. A patient who had started therapy for TB elsewhere but was not yet been started on ART was eligible for enrollment provided they did not have greater than 20 weeks of TB therapy. Delay between starting TB treatment and ART was not encouraged, and local or international guidelines should be followed for managing TB and HIV coinfection in infants and children.
• Female participant who was of child bearing potential and sexually active agreed to use two reliable methods of contraception, including a medically accepted barrier method of contraception (e.g., female/male condoms, diaphragm or cervical cap with a cream or gel that kills sperm (excluding nonoxydyl-9), intrauterine device \[IUD\], others) together with another reliable form of contraception while on study and for 4 weeks after stopping raltegravir.
• Parent, legal guardian, or designated guardian according to country-specific guidelines provided signed informed consent and to have the participant followed at the clinical site

You may not qualify if:

• Greater than or equal to Grade 2 aspartate aminotransferase (AST) or alanine aminotransferase (ALT) at screening, which must be within 30 days of entry. Note: Participants were allowed to be re-screened provided that they had at least 4 weeks of TB treatment remaining at the time of entry.
• Any greater than or equal to Grade 4 clinical toxicity or laboratory result at screening except fever, chills, fatigue or malaise, unintentional weight loss, and dyspnea or respiratory distress that could be associated with TB
• Acute, serious infections other than TB requiring active treatment (e.g., Pneumocystis jirovecii \[previously Pneumocystis carinii\] pneumonia \[PCP\], cryptococcal meningitis, etc.). Infants and children diagnosed with acute bacterial pneumonia at time of diagnosis of TB may be included. Prophylaxis against opportunistic infections was allowed.
• Diagnosis of Kwashiorkor (less than 80% expected weight-for-age with the presence of edema and hypoalbuminemia)
• Current chemotherapy for active malignancy and history of chemotherapy discontinued within 1 year of entry
• Rifampicin therapy of greater than 20 weeks duration immediately prior to enrollment
• Known or suspected multidrug resistant (MDR) or extensively drug resistant (XDR) TB, including contact with a documented MDR or XDR TB source case, as these may require longer duration of therapy or non-rifampicin containing regimen. Note: Participants found to have MDR or XDR TB before or during the study were informed of their illness and referred for appropriate care as determined by local guidelines.
• Current TB regimen containing rifabutin, macrolides, and any other anti-mycobacterial agents with known interactions with raltegravir
• Any clinically significant diseases (other than HIV and TB infection) or clinically significant findings during the screening medical history or physical examination that, in the investigator's opinion, would compromise the outcome of this study
• Participant who was pregnant or breastfeeding
• Participant who was unlikely to adhere to the study procedures or keep appointments
• Participant who was planning to relocate during the study to a non-IMPAACT study site
• Participant who was taking any disallowed medications.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (4)

Soweto IMPAACT CRS

Johannesburg, Gauteng, 1862, South Africa

Location

Wits RHI Shandukani Research Centre CRS

Johannesburg, Gauteng, 2001, South Africa

Location

Desmond Tutu TB Centre - Stellenbosch University (DTTC-SU) CRS

Cape Town, Western Cape, 7505, South Africa

Location

Famcru Crs

Cape Town, Western Cape, 7505, South Africa

Location

Related Publications (3)

• Lawn SD, Myer L, Bekker LG, Wood R. Burden of tuberculosis in an antiretroviral treatment programme in sub-Saharan Africa: impact on treatment outcomes and implications for tuberculosis control. AIDS. 2006 Aug 1;20(12):1605-12. doi: 10.1097/01.aids.0000238406.93249.cd.

  PMID: 16868441 BACKGROUND

• Walters E, Cotton MF, Rabie H, Schaaf HS, Walters LO, Marais BJ. Clinical presentation and outcome of tuberculosis in human immunodeficiency virus infected children on anti-retroviral therapy. BMC Pediatr. 2008 Jan 11;8:1. doi: 10.1186/1471-2431-8-1.

  PMID: 18186944 BACKGROUND

• Krogstad P, Samson P, Acosta EP, Moye J, Townley E, Bradford S, Brown E, Denson K, Graham B, Hovind L, Sise T, Teppler H, Mathiba SR, Fairlie L, Winckler JL, Slade G, Meyers T; International Maternal Pediatric Adolescent AIDS Clinical Trials Network P1101 Team. Pharmacokinetics and Safety of a Raltegravir-Containing Regimen in Children Aged 4 Weeks to 2 Years Living With Human Immunodeficiency Virus and Receiving Rifampin for Tuberculosis. J Pediatric Infect Dis Soc. 2021 Mar 26;10(2):201-204. doi: 10.1093/jpids/piaa039.

  PMID: 32448902 DERIVED

Related Links

• Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 2.0, November 2014

MeSH Terms

Conditions

HIV Infections; Tuberculosis

Interventions

Raltegravir Potassium

Condition Hierarchy (Ancestors)

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; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses

Intervention Hierarchy (Ancestors)

Pyrrolidinones; Pyrrolidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Melissa Allen, Director, IMPAACT Operations Center
• Organization: Family Health International (FHI 360)

mallen@fhi360.org

(919) 544-7040

Study Officials

• Tammy Meyers, MD

  Bamboo Grove, Wan Chai, Hong Kong, People's Republic of China

  STUDY CHAIR

• Paul Krogstad, MD

  University of California, Los Angeles

  STUDY CHAIR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 14, 2012
• First Posted: December 18, 2012
• Study Start: November 12, 2014
• Primary Completion: November 27, 2019
• Study Completion: November 27, 2019
• Last Updated: November 5, 2021
• Results First Posted: December 21, 2020

Record last verified: 2020-11

Locations

ZA (4)