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HIV InfectionsPhase 1/2NCT01751568

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

A Phase 1/2 study testing Raltegravir in people with HIV Infections and Tuberculosis, run by National Institute of Allergy and Infectious Diseases (NIAID) at 4 sites in South Africa.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 4 weeks to 11 years
Conditions the study is for
HIV Infections, Tuberculosis
What is being tested?
Raltegravir
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
40 participants
Where
4 sitesSouth Africa
Study dates
12 Nov 2014to 27 Nov 2019
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 4 weeks to 11 years
  • All sexes
  • No healthy volunteers
  • Child

Who may be able to join

  • 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)
Show all 10Show fewer
  • 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

Who cannot join

  • 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
Show all 13Show fewer
  • 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.

Trial locations and contacts

4 sites in 1 country.

South Africa4 sites

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

    Cape Town, Western Cape, 7505

  • Famcru Crs

    Cape Town, Western Cape, 7505

  • Soweto IMPAACT CRS

    Johannesburg, Gauteng, 1862

  • Wits RHI Shandukani Research Centre CRS

    Johannesburg, Gauteng, 2001

Other trials in South Africa

About this study

Official title: 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

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.

Read the 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 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.

Being tested
Raltegravir
Medical subject headings
HIV Infections, Tuberculosis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • RaltegravirDrug

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

Study groups in NCT01751568
Study groupRoleWhat they receive
Cohort 1: ≥ 2 to < 6 years of age on TB treatmentExperimentalParticipants 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.
Receives: Drug: Raltegravir
Cohort 2: ≥ 6 to < 12 years of age on TB treatmentExperimentalParticipants 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.
Receives: Drug: Raltegravir
Cohort 3: : ≥ 4 weeks to < 2 years of age on TB treatmentExperimentalParticipants 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.
Receives: Drug: Raltegravir

What is being measured

The primary outcome is the main question the study is designed to answer.

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

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

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

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

  5. 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.

    Measured: 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.

  6. 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.

    Measured: 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)

  1. 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: Measured at Week 8

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

    Number (Frequency) of participants who developed of new opportunistic infection(s) (OIs)

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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted18 Dec 2012 (estimated)
  2. Study start12 Nov 2014
  3. Primary completion27 Nov 2019
  4. Study completion27 Nov 2019

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
40 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01751568
Sponsor's protocol ID
P1101
Other IDs
11831, IMPAACT P1101
Status last verified
Nov 2020
First submitted
14 Dec 2012
Last updated
5 Nov 2021
Data monitoring committee
Yes

Publications

  • 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.

    PubMed 16868441

  • 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.

    PubMed 18186944

  • 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.

    PubMed 32448902

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Raltegravir in people with HIV Infections and Tuberculosis, run by National Institute of Allergy and Infectious Diseases (NIAID) at 4 sites in South Africa.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 10 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 5 Nov 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 4 sites in South Africa. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 21 Dec 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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 (time frame: Measured from the first dose of raltegravir through the participant's last study visit (median of 34 weeks)). The study lists 6 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01751568, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Nov 2021.

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