Safety of and Immune Response to Dolutegravir in HIV-1 Infected Infants, Children, and Adolescents

NCT01302847 | Completed Phase 1 Results DMC

• 4 other identifiers: P1093117732010-020988-20IMPAACT P1093
• Study Type: interventional
• Target: 181
• Locations: 8 countries
• Sites: 33

Brief Summary

Dolutegravir (DTG) is an HIV drug in the integrase inhibitor drug class. This study evaluated the pharmacokinetics (PK), safety, tolerability of and immune response to DTG when used concurrently with optimized background therapy (OBT) in HIV-1 infected infants, children, and adolescents.

Conditions

HIV Infections

Keywords

Integrase Inhibitors; Infant; Child; Adolescent

Outcome Measures

Primary Outcomes (5)

• Percentage of Participants With Grade 3 or Higher Adverse Events (AEs)

  All grade 3 or higher signs/symptoms, diagnoses, and laboratory AEs were included. AE grading was based on DAIDS AE Grading Table, Version 1.0, December 2004 (Clarification, August 2009). A 2-sided 95% Confidence Interval (CI) was calculated for the percentage using the binominal exact method.

  From treatment initiation through Weeks 24 and 48

• Percentage of Participants With Grade 3 or Higher Adverse Events (AEs) Assessed as Related to Study Drug

  All grade 3 or higher signs/symptoms, diagnoses, and laboratory AEs were included. AE grading was based on DAIDS AE Grading Table, Version 1.0, December 2004 (Clarification, August 2009). A 2-sided 95% Confidence Interval (CI) was calculated for the percentage using the binominal exact method.

  From treatment initiation through Weeks 24 and 48

• Number of Participants With Permanent Discontinuation of Study Drug Due to Adverse Events (AEs) Assessed as Related to Study Drug

  Number of participants with permanent discontinuation of study drug due to AEs assessed by the site investigator as related to the study drug.

  From treatment initiation through Weeks 24 and 48

• Number of Participants Who Died

  Number of participants who died were summarized

  From treatment initiation through Weeks 24 and 48

• PK Parameter: Area-under-the-curve From 0 to 24 Hours (AUC0-24)

  Pharmacokinetic parameters were determined from plasma concentration-time profiles using non-compartmental methods (Phoenix WinNonlin 8.0 or current, Certara, Princeton, NJ). AUC0-24 was determined using linear up-log down estimation in WinNonlin.

  One intensive PK visit between 5 and 10 days of DTG initiation. At intensive PK visit, blood samples were drawn pre-dose and at 1, 2, 3, 4, 6, 8 and 24 hours post dosing

Secondary Outcomes (25)

• Percentage of Participants With Grade 3 or Higher Adverse Events (AEs)

  From treatment initiation through Week 192. AEs after that time were censored.

• Percentage of Participants With Grade 3 or Higher Adverse Events (AEs) Assessed as Related to Study Drug

  From treatment initiation through Week 192. AEs after that time were censored.

• Number of Participants With Permanent Discontinuation of Study Drug Due to Adverse Events (AEs) Assessed as Related to Study Drug

  From treatment initiation through Week 192. AEs after that time were censored.

• Number of Participants Who Died

  From treatment initiation through Week 192. AEs after that time were censored.

• Percentage of Participants With Plasma HIV-1 RNA Less Than 400 Copies/ml

  Week 24 and Week 48

Study Arms (8)

Cohort I

EXPERIMENTAL

Adolescents 12 to younger than 18 years of age who received DTG film-coated tablets

Drug: DTG film-coated tablets

Cohort IIA

EXPERIMENTAL

Children 6 to younger than 12 years of age who received DTG film-coated tablets

Drug: DTG film-coated tablets

Cohort IIB

EXPERIMENTAL

Children 6 to younger than 12 years of age who received DTG granules for suspension

Drug: DTG granules for suspension

Cohort III

EXPERIMENTAL

Children 2 to younger than 6 years of age who received DTG granules for suspension

Drug: DTG granules for suspension

Cohort IV

EXPERIMENTAL

Children 6 months to younger than 2 years of age who received DTG granules for suspension

Drug: DTG granules for suspension

Cohort III-DT

EXPERIMENTAL

Children 2 to younger than 6 years of age who received DTG dispersible tablets

Drug: DTG dispersible tablets

Cohort IV-DT

EXPERIMENTAL

Children 6 months to younger than 2 years of age who received DTG dispersible tablets

Drug: DTG dispersible tablets

Cohort V-DT

EXPERIMENTAL

Infants 4 weeks to younger than 6 months of age who received DTG dispersible tablets

Drug: DTG dispersible tablets

Interventions

DTG film-coated tablets DRUG

DTG film-coated tablets initial starting dose at \~1 mg/kg with a maximum dose of 50 mg; orally once daily. Participants weighing ≥ 35kg received the proposed dose of 50 mg of DTG film-coated tablets.

Cohort I; Cohort IIA

DTG granules for suspension DRUG

DTG granules for suspension initial starting dose at \~0.64 mg/kg with a maximum dose of 32 mg; orally once daily.

Cohort IIB; Cohort III; Cohort IV

DTG dispersible tablets DRUG

DTG dispersible tablets initial starting dose of \~0.8 mg/kg with a maximum dose of 30 mg; orally once daily. The proposed weight-band dosing was: Weight band 3 to \<6 kg: 5 mg DTG dispersible tablets; Weight band 6 to \<10 kg: 15 mg DTG dispersible tablets; Weight band 10 to \<14 kg: 20 mg DTG dispersible tablets; Weight band 14 to \<20 kg: 25 mg DTG dispersible tablets; Weight band ≥20 kg: 30 mg DTG dispersible tablets.

Cohort III-DT

Eligibility Criteria

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

You may qualify if:

• Confirmed HIV-1 infection, defined as positive results from two samples collected at different time points (see protocol for more information)
• Participant belonged to one of the ARV exposure groups below:
• ARV-treatment experienced (not including receipt of ARVs as prophylaxis or for prevention of perinatal transmission)
• Previously took ARVs for treatment, but not taking ARVs at study screening.
• Had been off treatment for greater than or equal to 4 weeks prior to screening, OR
• At screening, taking ARVs for treatment but failing.
• Was on an unchanged, failing therapeutic regimen within the 4 to 12 weeks prior to screening (less than or equal to 1 log drop in HIV-1 RNA within the 4 to 12 weeks prior to screening). OR
• For participants less than 2 years of age, initiated ARVs for treatment less than 4 weeks prior to screening.
• ARV treatment naive (no exposure to ARVs for treatment; could have received ARVs for prophylaxis or prevention of perinatal transmission)
• If an infant had received nevirapine (NVP) as prophylaxis to prevent perinatal transmission, he or she did not receive NVP for at least 14 days prior to enrollment into Stage I or II.
• HIV-1 RNA viral load greater than 1,000 copies/mL of plasma at screening.
• Demonstrated ability or willingness to swallow assigned study medications.
• Parent or legal guardian were able and willing to provide signed informed consent.
• Female participants of reproductive potential, defined as having reached menarche, and who were engaging in sexual activity that could lead to pregnancy, agreed to use two contraceptive methods while on study and for two weeks after stopping study drug.
• Males engaging in sexual activity that could lead to HIV-1 transmission agreed to use a condom.

You may not qualify if:

• Presence of any active AIDS-defining opportunistic infection
• At enrollment, participant less than 3.0 kg
• Known Grade 3 or greater of any of the following laboratory toxicities within 30 days prior to study entry: neutrophil count, hemoglobin, platelets, aspartate aminotransferase (AST), alanine transaminase (ALT), lipase, serum creatinine and total bilirubin. A single repeat within the 30 days is allowed for eligibility determination. NOTE: Grade 3 total bilirubin was allowable, if the participant was on atazanavir (ATV).
• ANY known Grade 4 laboratory toxicities within 30 days prior to study entry. NOTE: Grade 4 total bilirubin was allowable, if the participant was on ATV.
• The following liver toxicities within 30 days prior to study entry: ALT greater than 3x the upper limit of normal (ULN) AND direct bilirubin was greater than 2x ULN
• Any prior history of malignancy, with the exception of localized malignancies such as squamous cell or basal cell carcinoma of the skin
• Clinical or symptomatic evidence of pancreatitis, as determined by the clinician
• Use of any disallowed medications at time of screening (see the protocol for a complete list of disallowed medications)
• Known history of exposure to integrase inhibitor treatment by the participant or participant's mother prior to delivery/cessation of breastfeeding
• Known resistance to an integrase inhibitor
• Women who were pregnant or breastfeeding
• At screening/entry, participating in or had participated in a study with a compound or device that was not commercially available within 30 days of signing informed consent, unless permission from both Protocol Teams was granted
• Participant was unlikely to adhere to the study procedures, keep appointments, or was planning to relocate during the study to a non-IMPAACT study site
• Any clinically significant diseases (other than HIV 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
• At screening/entry had used, or anticipated using, chronic systemic immunosuppressive agents or systemic interferon (e.g., for treatment of hepatitis C virus \[HCV\] infection) within 30 days prior to beginning DTG study treatment. Systemic corticosteroids (e.g., prednisone or equivalent up to 2 mg/kg/day) for replacement therapy or short courses (less than or equal to 30 days) were permitted. (See protocol for more information on disallowed medications.)

Sponsors & Collaborators

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

Study Sites (33)

University of California, UC San Diego CRS- Mother-Child-Adolescent HIV Program (Site ID: 4601)

La Jolla, California, 92093-0672, United States

Location

Miller Children's Hosp. Long Beach CA NICHD CRS (Site ID: 5093)

Long Beach, California, 90806, United States

Location

David Geffen School of Medicine at UCLA NICHD CRS (Site ID: 5112)

Los Angeles, California, 90095-1752, United States

Location

Univ. of California San Francisco NICHD CRS (Site ID: 5091)

San Francisco, California, 94143, United States

Location

Univ. of Colorado Denver NICHD CRS (Site ID: 5052)

Aurora, Colorado, 80045, United States

Location

Howard Univ. Washington DC NICHD CRS (Site ID: 5044)

Washington D.C., District of Columbia, 20060, United States

Location

South Florida CDTC Ft Lauderdale NICHD CRS (Site ID: 5055)

Fort Lauderdale, Florida, 33316, United States

Location

USF - Tampa NICHD CRS (Site ID: 5018)

Tampa, Florida, 33606, United States

Location

Rush Univ. Cook County Hosp. Chicago NICHD CRS (Site ID: 5083)

Chicago, Illinois, 60612, United States

Location

Lurie Children's Hospital of Chicago (LCH) CRS (Site ID: 4001)

Chicago, Illinois, 60614-3393, United States

Location

Children's Hosp. of Boston NICHD CRS (Site ID: 5009)

Boston, Massachusetts, 02115, United States

Location

Boston Medical Center Ped. HIV Program NICHD CRS (Site ID: 5011)

Boston, Massachusetts, 02118, United States

Location

Metropolitan Hosp. NICHD CRS (Site ID: 5003)

New York, New York, 10029, United States

Location

Bronx-Lebanon Hospital Center NICHD CRS (Site ID: 5114)

The Bronx, New York, 10457, United States

Location

Jacobi Med. Ctr. Bronx NICHD CRS (Site ID: 5013)

The Bronx, New York, 10461, United States

Location

DUMC Ped. CRS (Site ID: 4701)

Durham, North Carolina, 27710, United States

Location

Seattle Children's Research Institute CRS (Site ID: 5017)

Seattle, Washington, 98101, United States

Location

Gaborone CRS (Site ID: 12701)

Gaborone, South-East District, Botswana

Location

Molepolole CRS (Site ID: 12702)

Gaborone, Botswana

Location

SOM Federal University Minas Gerais Brazil NICHD CRS (Site ID: 5073)

Belo Horizonte, Minas Gerais, 30.130-100, Brazil

Location

Hospital Federal dos Servidores do Estado NICHD CRS (Site ID: 5072)

Rio de Janeiro, 20221-903, Brazil

Location

Instituto de Puericultura e Pediatria Martagao Gesteira - UFRJ NICHD CRS (Site ID: 5071)

Rio de Janeiro, 21941-612, Brazil

Location

Hosp. Geral De Nova Igaucu Brazil NICHD CRS (Site ID: 5097)

Rio de Janeiro, 26030, Brazil

Location

Univ. of Sao Paulo Brazil NICHD CRS (Site ID: 5074)

São Paulo, 14049-900, Brazil

Location

Kenya Medical Research Institute / Walter Reed Project Clinical Research Center, Kericho CRS (Site ID: 5121)

Kericho, 20200, Kenya

Location

Wits RHI Shandukani Research Centre CRS (Site ID: 8051)

Johannesburg, Gauteng, 2001, South Africa

Location

Umlazi CRS (Site ID: 30300)

Durban, KwaZulu-Natal, 4001, South Africa

Location

FAMCRU CRS (Site ID: 8950)

Tygerberg, Western Cape, 7505, South Africa

Location

Kilimanjaro Christian Medical Centre (KCMC) (Site ID: 5118)

Moshi, Tanzania

Location

Siriraj Hospital, Mahidol University NICHD CRS (Site ID: 5115)

Bangkok, Bangkoknoi, 10700, Thailand

Location

Chiangrai Prachanukroh Hospital NICHD CRS (Site ID: 5116)

Chiang Mai, 50100, Thailand

Location

Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS (Site ID: 31784)

Chiang Mai, 50200, Thailand

Location

Harare Family Care CRS (Site ID: 31890)

Harare, Zimbabwe

Location

Related Publications (6)

• Bennetto-Hood C, Tabolt G, Savina P, Acosta EP. A sensitive HPLC-MS/MS method for the determination of dolutegravir in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci. 2014 Jan 15;945-946:225-32. doi: 10.1016/j.jchromb.2013.11.054. Epub 2013 Dec 3.

  PMID: 24361860 BACKGROUND

• Viani RM, Alvero C, Fenton T, Acosta EP, Hazra R, Townley E, Steimers D, Min S, Wiznia A; P1093 Study Team. Safety, Pharmacokinetics and Efficacy of Dolutegravir in Treatment-experienced HIV-1 Infected Adolescents: Forty-eight-week Results from IMPAACT P1093. Pediatr Infect Dis J. 2015 Nov;34(11):1207-13. doi: 10.1097/INF.0000000000000848.

  PMID: 26244832 BACKGROUND

• Viani RM, Ruel T, Alvero C, Fenton T, Acosta EP, Hazra R, Townley E, Palumbo P, Buchanan AM, Vavro C, Singh R, Graham B, Anthony P, George K, Wiznia A; P1093 Study Team. Long-Term Safety and Efficacy of Dolutegravir in Treatment-Experienced Adolescents With Human Immunodeficiency Virus Infection: Results of the IMPAACT P1093 Study. J Pediatric Infect Dis Soc. 2020 Apr 30;9(2):159-165. doi: 10.1093/jpids/piy139.

  PMID: 30951600 BACKGROUND

• Ruel TD, Acosta EP, Liu JP, Gray KP, George K, Montanez N, Popson S, Buchanan AM, Bartlett M, Dayton D, Anthony P, Brothers C, Vavro C, Singh R, Koech L, Vhembo T, Mmbaga BT, Pinto JA, Dobbels EFM, Archary M, Chokephaibulkit K, Ounchanum P, Deville JG, Hazra R, Townley E, Wiznia A; IMPAACT P1093 team. 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. Lancet HIV. 2022 May;9(5):e332-e340. doi: 10.1016/S2352-3018(22)00044-3.

  PMID: 35489377 DERIVED

• Singh RP, Adkison KK, Baker M, Parasrampuria R, Wolstenholme A, Davies M, Sewell N, Brothers C, Buchanan AM. Development of Dolutegravir Single-entity and Fixed-dose Combination Formulations for Children. Pediatr Infect Dis J. 2022 Mar 1;41(3):230-237. doi: 10.1097/INF.0000000000003366.

  PMID: 34817414 DERIVED

• Vavro C, Ruel T, Wiznia A, Montanez N, Nangle K, Horton J, Buchanan AM, Stewart EL, Palumbo P. Emergence of Resistance in HIV-1 Integrase with Dolutegravir Treatment in a Pediatric Population from the IMPAACT P1093 Study. Antimicrob Agents Chemother. 2022 Jan 18;66(1):e0164521. doi: 10.1128/AAC.01645-21. Epub 2021 Oct 25.

  PMID: 34694878 DERIVED

Related Links

• The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 1.0, December 2004 (Clarification, August 2009).
• Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual), Version 2.0, January 2010

MeSH Terms

Conditions

HIV Infections

Interventions

Suspensions; dolutegravir

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

Intervention Hierarchy (Ancestors)

Colloids; Complex Mixtures; Dosage Forms; Pharmaceutical Preparations

Results Point of Contact

• Title: IMPAACT Clinicaltrials.gov Coordinator
• Organization: Family Health International (FHI 360)

MPAACT.ctgov@fstrf.org

(919) 405-1429

Study Officials

• Andrew Wiznia, M.D.

  Jacobi Medical Center

  STUDY CHAIR

• Theodore Ruel, M.D.

  University of California, San Francisco

  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: February 15, 2011
• First Posted: February 24, 2011
• Study Start: April 20, 2011
• Primary Completion: January 20, 2021
• Study Completion: October 18, 2023
• Last Updated: December 12, 2024
• Results First Posted: March 22, 2022

Record last verified: 2024-10

Locations

ZI (1); BR (5); ZA (3); BO (2); TA (1); US (17); KE (1); TH (3)