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

Study Overview
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Brief Summary
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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.

Detailed Description
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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 enrolled HIV-infected infants and children: who had never taken any ARV medications or who had not received ARVs for at least 30 days prior to study entry; and who were infected with TB and were taking or were starting a TB medication regimen that included rifampicin. The purpose of this study was to evaluate the safety and tolerance of raltegravir-containing ARV regimens to treat HIV when administered with a rifampicin-containing regimen used to treat TB in infants and children. Study researchers also evaluated the pharmacokinetics of the medications (i.e., how medication is absorbed and processed in the body) and determined the most effective dose of raltegravir when administered with a TB regimen that contains rifampicin. During the study, researchers continuously monitored participant data for safety and other factors. Researchers could adjust the dose of raltegravir given to a group of participants prior to enrolling additional participants. At study entry, participants underwent a medical and medication history review, physical examination, medication adherence assessment, blood collection, and urine collection. Participants received chewable raltegravir tablets twice daily, and they also took their TB medications, including rifampicin, and two nucleoside reverse transcriptase inhibitor (NRTI) ARV medications chosen by participants' doctors. This study provided raltegravir to participants; all other medications were prescribed by participants' own doctors. At a study visit at Days 5 to 8, participants remained in the clinic for about 12 hours. They took part in the same study procedures that occurred at the entry visit, but they also had 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 began receiving a fourth ARV medication chosen by their doctor, in addition to the other medications. Participants continued receiving raltegravir until they stopped taking their TB medications. They continued to take the third ARV medication and the other two ARV medications for three months after they stopped receiving raltegravir and the TB medications. Additional study visits occurred at Day 14, Weeks 4 and 8, every 4 weeks until the participant stopped receiving raltegravir and their TB medications, and 4 and 12 weeks after stopping raltegravir and the TB medications. These study visits included the same study procedures that occurred at study entry. Participants were expected to participate in the study for a total of about 4 to 9 months. Note that out of the forty (40) participants enrolled only (39) participants received the study treatment (raltegravir). The total enrollment for Cohort 1 was thirteen (13) participants, with only twelve (12) who received raltegravir. Therefore, the results of this submission is based on the 39 participants who received raltegravir.

Official Title
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Phase I/II Dose-Finding, Safety, Tolerance, and Pharmacokinetics Study of a Raltegravir-Containing Antiretroviral Therapy (ART) Regimen in HIV-Infected and TB Co-Infected Infants and Children

Conditions
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HIV Infections, Tuberculosis

Intervention / Treatment
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* Drug: Raltegravir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 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 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.

Ages Eligible for Study
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Minimum Age: 4 Weeks
Maximum Age: 11 Years

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: ≥ 2 to < 6 years of age on TB treatment<br>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<br>* Chewable raltegravir tablets, initially dosed at 12 mg/kg (up to a maximum of 800 mg) orally twice daily.<br>|
| Experimental: Cohort 2: ≥ 6 to < 12 years of age on TB treatment<br>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<br>* Chewable raltegravir tablets, initially dosed at 12 mg/kg (up to a maximum of 800 mg) orally twice daily.<br>|
| Experimental: Cohort 3: : ≥ 4 weeks to < 2 years of age on TB treatment<br>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<br>* Chewable raltegravir tablets, initially dosed at 12 mg/kg (up to a maximum of 800 mg) orally twice daily.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 
| 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) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | Number (Frequency) of Participants who failed to respond virologically at Week 8, which includes HIV RNA (copies/mL) greater than 400 copies/mL AND less than 1-log10 drop from baseline. Please note that the protocol definition of virologic response was: achieving at least a 1-log10 reduction from baseline in HIV-1 RNA (copies/mL) or HIV-1 RNA ≤ 400 copies/mL at week 8. An As-Treated (AT) analysis was carried out, such that participants who permanently discontinued treatment before week 8, without evaluable data were not included in the analyses. | Measured at Week 8 | 
| Number of Participants Who Developed of New Opportunistic Infection(s) (OIs) | Number (Frequency) 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) |