Evaluating the Safety, Tolerance, Drug Interactions, and Effective Dosing of a Raltegravir-Containing Antiretroviral Therapy (ART) Regimen in ART-Naive Children Infected With HIV and TB

This study is not yet open for participant recruitment.
Verified March 2014 by National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT01751568
First received: December 14, 2012
Last updated: March 18, 2014
Last verified: March 2014
  Purpose

People who are infected with HIV and tuberculosis (TB) need to receive medications that treat both diseases safely and effectively. This study will enroll children infected with HIV and TB and evaluate 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 will also determine the most effective dose of raltegravir for children when it is taken with rifampicin.


Condition Intervention Phase
HIV Infections
Tuberculosis
Drug: Raltegravir
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I/II Dose-Finding, Safety, Tolerance, Drug-Drug Interaction and Pharmacokinetics Study of a Raltegravir-Containing Antiretroviral Therapy (ART) Regimen in ART-Naive HIV-Infected and TB Co-Infected Children ≥ 3 Years to < 12 Years of Age

Resource links provided by NLM:


Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:
  • Termination from treatment due to a suspected adverse drug reaction (SADR), including death and adverse events of greater than or equal to Grade 3, attributable to raltegravir [ Time Frame: Measured through a participant's last study visit, at approximately Month 4 to 9 ] [ Designated as safety issue: Yes ]
  • Early termination of TB therapy if there is multi-drug-resistant (MDR)/extensively drug-resistant (XDR) TB detected subsequent to starting ARV treatment or if due to toxicity attributable to TB medication [ Time Frame: Measured through a participant's last study visit, at approximately Month 4 to 9 ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Failure to respond at Week 8, which includes HIV RNA (copies/mL) greater than 400 copies/mL AND less than 1-log10 drop from baseline [ Time Frame: Measured at Week 8 ] [ Designated as safety issue: No ]
  • Development of new opportunistic infections (OIs) [ Time Frame: Measured through a participant's last study visit, at approximately Month 4 to 9 ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 72
Study Start Date: July 2013
Estimated Primary Completion Date: March 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 3 to Less than 12 Years of Age
Participants will receive chewable raltegravir tablets, initially dosed at 12 mg/kg (up to a maximum of 800 mg) twice daily, in addition to two NRTIs to treat HIV and a rifampicin-containing regimen to treat TB. Participants will be enrolled into the study into two cohorts: Cohort I: 3 years of age to less than 6 years of age and Cohort II: 6 years of age to less than 12 years of age. After a study visit at Day 5 to 8, efavirenz will be added to the regimen.
Drug: Raltegravir
Chewable raltegravir tablets, initially dosed at 12 mg/kg (up to a maximum of 800 mg) twice daily.

Detailed Description:

People who are infected with HIV are also at risk for becoming infected with TB, particularly in many resource-limited settings, including Sub-Saharan Africa. Rifampicin is a medication commonly used to treat TB. There is a need for HIV treatment regimens that contain newer ARV medications that are well-tolerated and have minimal interactions with rifampicin-containing TB medication regimens. This study will enroll HIV-infected children who have never taken any ARV medications and who are infected with TB and are taking or will be starting a TB medication regimen that includes rifampicin. The purpose of this study is to evaluate the safety and tolerance of raltegravir-containing ARV regimens to treat HIV when administered with a rifampicin-containing regimen to treat TB in children. Study researchers will also evaluate the pharmacokinetics of the medications (i.e., how medication is absorbed and processed in the body) and determine the most effective dose of raltegravir when it is administered with a TB regimen that contains rifampicin.

During the study, researchers will continuously monitor participant data for safety and other factors. Researchers may adjust the dose of raltegravir given to participants prior to enrolling additional participants.

At study entry, participants will undergo a medical and medication history review, physical examination, medication adherence assessment, blood collection, and urine collection. Participants will receive chewable raltegravir tablets twice daily, and they will also take their TB medications, including rifampicin, and two nucleoside reverse transcriptase inhibitor (NRTI) ARV medications that will be chosen by participants' doctors. This study will provide raltegravir to participants; all other medications will be prescribed by participants' own doctors.

At study visits at Days 5 to 8 and at Week 4, participants will remain in the clinic for about 12 hours. During these two visits, participants will take part in the same study procedures that occurred at the entry visit, but they will also have small amounts of blood collected several times throughout the 12 hours to measure the amount of medication in the blood. After the Day 5 to 8 visit, participants will begin receiving efavirenz, which is an ARV medication, in addition to the other medications. Participants will continue receiving raltegravir until they stop taking their TB medications. They will continue to take efavirenz and the other two ARV medications for 3 months after they stop receiving raltegravir and the TB medications.

Additional study visits will occur at Week 8, every 4 weeks until the participant stops receiving raltegravir and the TB medications, and 4 and 12 weeks after stopping raltegravir and the TB medications. These study visits will include the same study procedures that occurred at study entry. Participants will be enrolled in the study for a total of about 4 to 9 months.

  Eligibility

Ages Eligible for Study:   3 Years to 11 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Weight greater than or equal to 10 kg at entry
  • Documentation of HIV-1 infection is 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 IMPAACT central laboratory. More information on this criterion can be found in the protocol.
  • ARV treatment naive, except for exposure to prevention of mother-to-child transmission (PMTCT); nevirapine (NVP) use for PMTCT cannot have extended beyond the first week of life
  • ARV treatment eligible as defined by:

    1. Country-specific guidelines OR
    2. World Health Organization (WHO) pediatric treatment algorithm (http://www.who.int/hiv/pub/guidelines/art/en/index.html)
  • Diagnosis of pulmonary TB or TB adenitis. More information on this criterion can be found in the protocol.
  • Initiated at least a 3-drug TB regimen containing rifampicin and has tolerated at least 1 week of TB drug regimen prior to initiation of raltegravir. Note: TB treatment may be started after being diagnosed by the site investigator. Treatment regimens may include isoniazid, pyrazinamide, ethambutol, and streptomycin in addition to rifampicin.
  • Parent, legal guardian, or designated guardian according to country-specific guidelines able and willing to provide signed informed consent and to have the participant followed at the clinical site

Exclusion Criteria:

  • 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 can be re-screened provided that they will have at least 4 weeks of TB treatment remaining at the time of entry.
  • Any greater than Grade 3 clinical toxicity 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.). Children diagnosed with acute bacterial pneumonia at time of diagnosis of TB may be included. Prophylaxis against opportunistic infections will be 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 MDR or 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 will be 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
  • Sexually active, pregnant, or breastfeeding
  • Unlikely to adhere to the study procedures or keep appointments
  • Planning to relocate during the study to a non-IMPAACT study site
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01751568

Locations
South Africa
Shandukani CRS Not yet recruiting
Johannesburg, Gauteng, South Africa, 2001
Contact: Hermien Gous, Pharm.D.    27-11-3585503    hgous@wrhi.ac.za   
Sponsors and Collaborators
Investigators
Study Chair: Tammy Meyers, MD Bamboo Grove, Wan Chai, Hong Kong, People's Republic of China
Study Chair: Paul Krogstad, MD University of California, Los Angeles
  More Information

Publications:
Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT01751568     History of Changes
Other Study ID Numbers: P1101, 11831, IMPAACT P1101
Study First Received: December 14, 2012
Last Updated: March 18, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Tuberculosis
HIV Infections
Acquired Immunodeficiency Syndrome
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Slow Virus Diseases
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections

ClinicalTrials.gov processed this record on April 20, 2014