Dolutegravir for Newborns Exposed to HIV

No longer recruiting at 20 trial locations

Overseen By Sarah Bradford, MPH

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Must be taking: ARV prophylaxis

Disqualifiers: Blood group incompatibility, Positive HIV test, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 5 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 16 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety and effectiveness of the drug Dolutegravir for newborns exposed to HIV. The goal is to determine if this anti-HIV treatment benefits infants whose mothers have HIV. The trial includes different groups, such as babies whose mothers took Dolutegravir shortly before birth and those whose mothers did not. This study may suit newborns who are healthy, weigh at least 2 kg at birth, and have mothers with confirmed HIV. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, providing the opportunity to be among the first to receive this treatment.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, it mentions that infants or breastfeeding mothers should not be receiving any disallowed medication, so it's best to discuss your current medications with the study team.

Is there any evidence suggesting that this trial's treatment is likely to be safe for newborns?

Research shows that dolutegravir, a drug used to treat HIV, has been tested on newborns and appears safe. In earlier studies, researchers administered two single doses of dolutegravir to newborns exposed to HIV, and they tolerated it well. Importantly, no unexpected side effects were reported. In one study, 57% of the 21 newborns experienced side effects, but these were expected and not serious.

These results suggest that dolutegravir is generally safe for newborns, but further research is needed to confirm this. Prospective participants should discuss any concerns with healthcare professionals before joining this type of trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about Dolutegravir for newborns exposed to HIV because it presents a new way to tackle the virus early on. Unlike other treatments that might not be suitable for infants, Dolutegravir is being studied in a liquid suspension form, which could be easier for newborns to take. This treatment also has the potential to be administered shortly after birth, which might help in reducing the risk of HIV transmission from mother to child at a crucial time. Additionally, Dolutegravir has shown promise in adults and older children for its effectiveness and safety, which raises hopes for similar outcomes in newborns.

What evidence suggests that Dolutegravir might be an effective treatment for newborns exposed to HIV?

Research shows that dolutegravir (DTG) is a powerful treatment for HIV. Studies have found that DTG-based treatments outperform older medications and can help prevent the spread of HIV from mother to baby. Specifically, babies born to mothers taking DTG were 44% less likely to contract HIV compared to those whose mothers used other treatments. Although a small risk of birth defects affecting the brain or spine exists in babies exposed to DTG, the benefits for controlling HIV are significant. This trial will enroll newborns in different cohorts to evaluate the pharmacokinetics (PK) and safety of DTG. Overall, DTG is a promising option for preventing HIV transmission to newborns. ^{6 7 8 9 10}

Who Is on the Research Team?

Diana Clarke, Pharm.D.

Principal Investigator

BMC/Dept. of Pharmacy

Are You a Good Fit for This Trial?

This trial is for newborn babies exposed to HIV-1, born at least 37 weeks into pregnancy and weighing at least 2 kg. They must be generally healthy with normal or slightly altered blood tests. Babies can participate if their mothers have confirmed HIV-1 but haven't taken Dolutegravir close to delivery. Mothers need legal capacity to consent.

Inclusion Criteria

My baby was born full-term and was not a twin or multiple.

My baby's birth weight was within the required range.

Mother is of legal age or circumstance to provide independent informed consent and is willing and able to provide written informed consent for her and permission for her infant's participation in this study

Exclusion Criteria

At entry, infant with a documented positive HIV nucleic acid test result

Mother or infant has any condition that, in the opinion of the site investigator or designee, would make participation in the study unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives

Known maternal-fetal blood group incompatibility

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Infants receive the study drug Dolutegravir to evaluate pharmacokinetics and safety

16 weeks

Regular visits for monitoring and drug administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Dolutegravir

Trial Overview The study tests the safety and dosage of an anti-HIV drug called Dolutegravir in two forms: oral suspension (0.5 mg/kg) and dispersible tablets (5 mg). It involves up to 108 mother-baby pairs from various countries, monitoring infants for about four months after birth.

How Is the Trial Designed?

Group I: Cohort 2 Experimental Treatment 2 Interventions

Cohort 2, Strata 2A and 2B, will be opened to accrual when the DTG dose and formulation to be administered for each stratum are established based on the PK and safety data from all Cohort 1 strata (Strata 1A and 1B, and 1C if applicable) and available data from other studies. * Stratum 2A (DTG-naïve): Infants with no in utero exposure to maternal DTG (no exposure to DTG during the two weeks prior to delivery) * Stratum 2B (DTG-exposed): Infants with in utero exposure to maternal DTG (mothers who receive at least one dose of DTG within 72 hours prior to delivery)

Group II: Cohort 1 Experimental Treatment 2 Interventions

Cohort 1 will be opened first to accrual, with Strata 1A and 1B being opened concurrently, to evaluate the PK and safety of two single DTG liquid suspension doses for the relevant stratum. Stratum 1C will only be opened to accrual if PK and safety data from Strata 1A and 1B infants support administration of DTG 5 mg DT across all neonates, or only in neonates with a minimum birth weight. * Stratum 1A (DTG-naïve): Infants with no in utero exposure to maternal DTG (no exposure to DTG during the two weeks prior to delivery) * Stratum 1B (DTG-exposed): Infants with in utero exposure to maternal DTG (mothers who receive at least one dose of DTG within 72 hours prior to delivery) * Stratum 1C (DTG-naïve): Infants with no in utero exposure to maternal DTG (no exposure to DTG during the two weeks prior to delivery).

Dolutegravir is already approved in European Union, United States, Canada, Japan, Switzerland for the following indications:

Approved in European Union as Tivicay for:

• HIV-1 infection

Approved in United States as Tivicay for:

• HIV-1 infection

Approved in Canada as Tivicay for:

• HIV-1 infection

Approved in Japan as Tivicay for:

• HIV-1 infection

Approved in Switzerland as Tivicay for:

• HIV-1 infection

Who Is Running the Clinical Trial?

National Institute of Allergy and Infectious Diseases (NIAID)

Lead Sponsor

Trials

3,361

Recruited

5,516,000+

ViiV Healthcare

Industry Sponsor

Trials

379

Recruited

479,000+

Founded

2009

Headquarters

London, England, UK

Known For

HIV Research

Top Products

- Tivicay (dolutegravir), - Triumeq (abacavir/dolutegravir/lamivudine), - Juluca (dolutegravir/rilpivirine), - Apretude (cabotegravir)

Dr. Harmony Garges

ViiV Healthcare

Chief Medical Officer

MD

Deborah Waterhouse

ViiV Healthcare

Chief Executive Officer since 2017

Bachelor's degree in Business Administration

National Institute of Mental Health (NIMH)

Collaborator

Trials

3,007

Recruited

2,852,000+

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Collaborator

Trials

2,103

Recruited

2,760,000+

Published Research Related to This Trial

Out of 249,066 individuals using Dolutegravir (DTG) in Brazil, only 1.39% reported adverse drug reactions (ADRs), indicating that DTG has good tolerability and safety among people living with HIV.

The majority of reported ADRs were mild and included gastrointestinal, neurological, and psychiatric issues, with serious ADRs being rare, suggesting that DTG is a safe treatment option overall.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Active Pharmacovigilance Project on the safety profile of Dolutegravir in Brazil. Mendes, JC., Ceccato, MDGB., Reis, AMM., et al.[2023]

In a study of 3,347 children living with HIV in Mozambique, the introduction of dolutegravir (DTG) led to high viral suppression rates of 79.7% for newly initiated patients and 85.8% for those switching to DTG after at least 6 months.

Despite achieving over 80% viral suppression, more than one-third of the children experienced multiple changes in their anchor drug, highlighting challenges in treatment stability that may be linked to drug stockouts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Virologic Outcomes and ARV Switch Profiles 2 Years After National Rollout of Dolutegravir to Children Less Than 15 Years in Southern Mozambique. Gill, MM., Herrera, N., Guilaze, R., et al.[2023]

In a multicenter phase I/II study involving pediatric participants aged 4 weeks to <18 years with HIV-1, treatment-emergent resistance to dolutegravir was observed in 8 participants, highlighting the need for monitoring resistance in highly treatment-experienced populations.

The study identified specific integrase resistance mutations (G118R and R263K) that reduced dolutegravir susceptibility and replication capacity, providing insights into the mechanisms of resistance that can inform future treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Emergence of Resistance in HIV-1 Integrase with Dolutegravir Treatment in a Pediatric Population from the IMPAACT P1093 Study. Vavro, C., Ruel, T., Wiznia, A., et al.[2022]

The study involved 181 participants aged 4 weeks to less than 6 years, and the proposed dosing of dolutegravir dispersible tablets achieved drug exposure levels similar to those in adults, indicating effective treatment potential for young children with HIV-1.

Dolutegravir was found to be safe and well tolerated, with no severe adverse events reported, supporting its use as a first-line or second-line treatment option for infants and young children living with HIV-1.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, safety, tolerability, and antiviral activity of dolutegravir dispersible tablets in infants and children with HIV-1 (IMPAACT P1093): results of an open-label, phase 1-2 trial. Ruel, TD., Acosta, EP., Liu, JP., et al.[2023]

A study using population pharmacokinetic modeling found that a 5-mg dose of dolutegravir (DTG) for newborns, given at birth and again after 48 hours, effectively maintains drug concentrations within the safe target range for DTG-naïve infants.

For infants exposed to DTG in utero, administering a 5-mg dose at 24 hours after birth also keeps drug levels within or nearly within the target range, highlighting the importance of maternal DTG dosing history in determining safe neonatal dosing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimizing Dolutegravir Initiation in Neonates Using Population Pharmacokinetic Modeling and Simulation. Piscitelli, J., Nikanjam, M., Best, BM., et al.[2023]

A physiologically based pharmacokinetic (PBPK) model successfully predicted the pharmacokinetics of dolutegravir in neonates, suggesting that a dosing regimen of 5 mg every 48 hours during the first 3 weeks of life could achieve effective plasma levels for treating and preventing HIV.

The model was validated using clinical data for other drugs, showing that the predicted exposure levels of dolutegravir are consistent with those observed in pediatric patients, indicating its potential safety and efficacy for neonatal use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prediction of dolutegravir pharmacokinetics and dose optimization in neonates via physiologically based pharmacokinetic (PBPK) modelling. Bunglawala, F., Rajoli, RKR., Mirochnick, M., et al.[2021]

A study involving 239 participants aged 0.1 to 17.5 years demonstrated that dolutegravir dosing in children provides similar drug exposure levels to those seen in adults, supporting its use as a safe and effective treatment for HIV.

The pharmacokinetic model showed that body weight, age, and formulation significantly influence dolutegravir levels in children, but no safety concerns or adverse events were linked to the drug exposure, reinforcing its tolerability.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population Pharmacokinetic Modeling of Dolutegravir to Optimize Pediatric Dosing in HIV-1-Infected Infants, Children, and Adolescents. Chandasana, H., Thapar, M., Hayes, S., et al.[2023]

In a study of 50 perinatally HIV-1-infected adolescents, dolutegravir-based regimens achieved and maintained virological suppression (plasma viral load <50 copies/mL) in 66% of patients, demonstrating its efficacy in this population.

Dolutegravir was well tolerated, with only one patient discontinuing treatment due to severe side effects, and no resistance mutations were observed in those who experienced virological failure, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and tolerance of dolutegravir-based combined ART in perinatally HIV-1-infected adolescents: a French multicentre retrospective study. Briand, C., Dollfus, C., Faye, A., et al.[2020]

Dolutegravir is an effective treatment for HIV-1, showing noninferior efficacy compared to other antiretroviral therapies in both treatment-naïve and experienced patients, based on data from 6 clinical trials.

It demonstrates significant potency in patients with multiple-class antiretroviral resistance, achieving a 63% virologic suppression rate by week 8, indicating its potential as a reliable option even in challenging cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dolutegravir: An Integrase Strand Transfer Inhibitor for the Treatment of Human Immunodeficiency Virus 1 in Adults. Mercadel, CJ., Skelley, JW., Kyle, JA., et al.[2023]

Dolutegravir is a new HIV-1 treatment that can be taken once daily without needing additional boosting, showing high effectiveness in achieving viral suppression in both treatment-naive and treatment-experienced patients.

In clinical trials, dolutegravir demonstrated superior or noninferior efficacy compared to other antiretroviral therapies, with a high barrier to resistance and a favorable safety profile, making it a significant option for HIV-1 treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dolutegravir: a review of its use in the management of HIV-1 infection in adolescents and adults. McCormack, PL.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6125741/

Evaluating outcomes of mother–infant pairs using ... The study found a risk of neural tube defects of 0.9% (4/426) among infants exposed to DTG compared with 0.1% for infants exposed to other antiretrovirals (ART) ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12506683/

The Effects on the Growth of HIV-exposed Uninfected ... In this prespecified secondary analysis, we compared growth trajectories over the first 72 weeks of life in HIV-exposed uninfected infants ...

3. clinicalinfo.hiv.gov clinicalinfo.hiv.gov/sites/default/files/guidelines/documents/perinatal-hiv/safety-toxicity-arv-agents-integrase-inhibitors-dolutegravir-tivicay-perinatal.pdf

Perinatal Guidelines - Dolutegravir (Tivicay, Tivicay PD, DTG) Evaluating outcomes of mother-infant pairs using dolutegravir for HIV treatment during pregnancy. AIDS. 2018;32(14):2017-2021. Available at ...

4. journals.sagepub.com journals.sagepub.com/doi/10.1177/09564624251361183?int.sj-full-text.similar-articles.7

Effectiveness of dolutegravir based antiretroviral treatment ... Dolutegravir-based ART is more effective than earlier regimens and promises to achieve the elimination of pediatric HIV. Introduction.

5. dovepress.com dovepress.com/effect-of-dolutegravir-based-first-line-antiretroviral-therapy-on-moth-peer-reviewed-fulltext-article-HIV

HIV-exposed infant DTG-based therapy for HIV transmission Women receiving DTG-based first-line ART were 44% less likely to transmit the virus to their infants than those receiving EFV-based regimens ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/41075812/

Safety and pharmacokinetics of dolutegravir dispersible ... A total of 22 adverse events occurred in 12 (57%) of the 21 neonates receiving dolutegravir dispersible tablets and 23 adverse events occurred ...

7. sciencedirect.com sciencedirect.com/science/article/abs/pii/S2352301825002395

Safety and pharmacokinetics of dolutegravir dispersible ... A total of 22 adverse events occurred in 12 (57%) of the 21 neonates receiving dolutegravir dispersible tablets and 23 adverse events occurred ...

8. impaactnetwork.org impaactnetwork.org/sites/default/files/IMPAACT2023_HIVPeds2024_Corrected_31JUL2024.pdf

Pharmacokinetics and Safety of Dolutegravir in Neonates ... Two single doses of DTG, on top of SoC ARV prophylaxis, were well-tolerated with no unexpected adverse events in neonates exposed to HIV-1. • Simulations show ...

9. clinicaltrials.gov clinicaltrials.gov/study/NCT05406583?term=pharmacology%20%2B%20NICHD&viewType=Table&rank=7

NCT05406583 | A Study of the Safety, Tolerability, and ... This study will test an anti-HIV drug (ARV) for newborn babies. The study will include a minimum of 36 and up to 108 mothers living with HIV and their ...

10. thelancet.com thelancet.com/journals/lanhiv/article/PIIS2352-3018(25)00239-5/abstract

Safety and pharmacokinetics of dolutegravir dispersible ... A total of 22 adverse events occurred in 12 (57%) of the 21 neonates receiving dolutegravir dispersible tablets and 23 adverse events occurred ...