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Dolutegravir Pediatric Liquid Formulation Study

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03921723
Recruitment Status : Completed
First Posted : April 19, 2019
Last Update Posted : September 23, 2019
Sponsor:
Information provided by (Responsible Party):
ViiV Healthcare

Brief Summary:
This is an open-label, single-center, single dose, non-randomized, sequential, fixed-sequence study, which will evaluate pharmacokinetics (PK) of dolutegravir (DTG) in healthy adult subjects. The study will contain 6 periods with five prototype liquid formulations for evaluation in fasted state. In period 1, 2 and 3 single reference dose of 2 dispersible tablets of 5 milligram DTG will be administered and at least 2 liquid prototype DTG formulations (containing a target total dose of 10mg DTG). There will be a wash-out period of 7 days between each period. In period 4 through 6, there would be options to evaluate additional prototype liquid formulations. The total duration of study will be up to 17 weeks. DTG has been found to be safe and effective in adults infected with human immunodeficiency virus (HIV), and DTG liquid formulation are being developed for the treatment of HIV-infected pediatric subjects who weigh less than 25 kilograms (Kgs). Approximately 18 subjects will be enrolled in this study.

Condition or disease Intervention/treatment Phase
HIV Infections Drug: Dolutegravir dispersible tablet Drug: Dolutegravir oral suspension Drug: Dolutegravir oral solution Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 22 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: The study is non-randomized 6 period, 6 way fixed sequential design.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Non-randomized, Sequential, Fixed-sequence Evaluation of Prototype Dolutegravir Liquid Formulations Versus 5mg Dolutegravir Dispersible Tablets Following Single-dose Fasted-state Administrations to Normal Healthy Adult Participants
Actual Study Start Date : May 7, 2019
Actual Primary Completion Date : July 25, 2019
Actual Study Completion Date : July 25, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS

Arm Intervention/treatment
Experimental: Subject receiving Dolutegravir 10 mg
Subject will receive a prototype equivalent to DTG 10 mg liquid formulation in period 1, a prototype equivalent to DTG 10 mg liquid formulation in period 2, a DTG 10 mg dispersible tablet in Period 3, each period will be separated by washout period of >= 7 days, if required a prototype equivalent to DTG 10 mg liquid formulation in period 4, a prototype equivalent to DTG 10 mg liquid formulation in period 5, and a prototype equivalent to DTG 10 mg liquid formulation in period 6 will be evaluated.
Drug: Dolutegravir dispersible tablet
DTG will be available as an oral tablet with dosing strength of 5 mg 2 tablet will be dispersed in water will be administered orally for prescribed regimen.

Drug: Dolutegravir oral suspension
DTG will be available as an oral suspension with dosing strength of 5 mg per milliliter (ml) or 2 mg per ml with miglyol 812N or ethyl cellulose in miglyol 812N as vehicle for suspension administered orally for prescribed regimen.

Drug: Dolutegravir oral solution
DTG will be available as an oral solution with dosing strength of 2 mg per ml will be administered orally for prescribed regimen.




Primary Outcome Measures :
  1. Area under the plasma concentration time curve from time zero to the last quantifiable time point (AUC[0-t]) following administration of DTG [ Time Frame: Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 48 and 72 hours post-dose ]
    Blood samples will be collected for pharmacokinetic analysis of DTG

  2. AUC from time zero to infinity (0-inf) following administration of DTG [ Time Frame: Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 48 and 72 hours post-dose ]
    Blood samples will be collected for pharmacokinetic analysis of DTG

  3. Maximum observed concentration (Cmax) following administration of DTG [ Time Frame: Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 48 and 72 hours post-dose ]
    Blood samples will be collected for pharmacokinetic analysis of DTG


Secondary Outcome Measures :
  1. Absorption lag time (tlag) following administration of DTG [ Time Frame: Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 48 and 72 hours post-dose ]
    Blood samples will be collected for pharmacokinetic analysis of DTG

  2. Time of maximum observed concentration (tmax) following administration of DTG [ Time Frame: Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 48 and 72 hours post-dose ]
    Blood samples will be collected for pharmacokinetic analysis of DTG

  3. Time of last quantifiable concentration (t) following administration of DTG [ Time Frame: Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 48 and 72 hours post-dose ]
    Blood samples will be collected for pharmacokinetic analysis of DTG

  4. Elimination half-life (t½) following administration of DTG [ Time Frame: Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 48 and 72 hours post-dose ]
    Blood samples will be collected for pharmacokinetic analysis of DTG

  5. Apparent elimination rate constant (lambda z) following administration of DTG [ Time Frame: Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 48 and 72 hours post-dose ]
    Blood samples will be collected for pharmacokinetic analysis of DTG

  6. Percentage of AUC(0-inf) extrapolated (%AUCex) following administration of DTG [ Time Frame: Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 48 and 72 hours post-dose ]
    Blood samples will be collected for pharmacokinetic analysis of DTG

  7. AUC from time zero to 24 hours (AUC[0-24]) following administration of DTG [ Time Frame: Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 48 and 72 hours post-dose ]
    Blood samples will be collected for pharmacokinetic analysis of DTG

  8. AUC from time zero to 72 hours (AUC[0-72]) following administration of DTG [ Time Frame: Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 48 and 72 hours post-dose ]
    Blood samples will be collected for pharmacokinetic analysis of DTG

  9. Apparent oral clearance (CL/F) following administration of Dolutegravir [ Time Frame: Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 48 and 72 hours post-dose ]
    Blood samples will be collected for pharmacokinetic analysis of Dolutegravir

  10. Apparent oral volume of distribution (Vz/F) following administration of Dolutegravir [ Time Frame: Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 48 and 72 hours post-dose ]
    Blood samples will be collected for pharmacokinetic analysis of Dolutegravir

  11. Last quantifiable concentration (Ct) following administration of Dolutegravir [ Time Frame: Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 48 and 72 hours post-dose ]
    Blood samples will be collected for pharmacokinetic analysis of Dolutegravir

  12. Concentration at 24h post-dose (C24) following administration of Dolutegravir [ Time Frame: Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 48 and 72 hours post-dose ]
    Blood samples will be collected for pharmacokinetic analysis of Dolutegravir

  13. Change from Baseline in blood pressure [ Time Frame: Baseline and Up to Week 10 ]
    Systolic and diastolic blood pressure of subjects will be measured in a supine position after at least 5 minutes of rest with a completely automated device.

  14. Change from Baseline in heart rate [ Time Frame: Baseline and Up to Week 10 ]
    Heart rate of subjects will be measured in a supine position after at least 5 minutes of rest.

  15. Number of subjects with adverse events and serious adverse events [ Time Frame: Up to Week 10 ]
    An adverse event is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. Any untoward medical occurrence resulting in death, life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment will be categorized as serious adverse event.

  16. Number of subjects with toxicity grading for hematology parameters [ Time Frame: Up to Week 10 ]
    Blood samples will be collected from subjects for the analysis of hematology parameters as a measure of safety, including platelet count, red blood cell, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, percent reticulocytes, neutrophils, lymphocytes, monocytes, eosinophils, and basophils.

  17. Number of subjects with toxicity grading for clinical chemistry parameters [ Time Frame: Up to Week 10 ]
    Blood samples will be collected from subjects for the analysis of clinical chemistry parameters as a measure of safety, including blood urea nitrogen, potassium, aspartate aminotransferase, total bilirubin, indirect bilirubin, direct bilirubin, albumin, creatinine, sodium, alanine aminotransferase, total protein, glucose (fasted), calcium, alkaline phosphatase, and creatine kinase.

  18. Number of subjects with toxicity grading for urine parameters [ Time Frame: Up to Week 10 ]
    Urine samples will be collected from subjects for the analysis of urinalysis parameters as a measure of safety, including specific gravity and potential of hydrogen (pH) of urine, presence of glucose, protein, blood, and ketones in urine by dipstick test. Microscopic examination will be performed if blood or protein is abnormal.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Subject must be 18 to 55 years of age inclusive, at the time of signing the informed consent.
  • Subjects who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, and cardiac evaluation.
  • Body weight >= 50 kg (110 pounds [lbs]) for men and >=45 kg (99 lbs) for women and body mass index (BMI) within the range 18.5-31.0 kilogram per meter square (kg/m^2) (inclusive).
  • Male and female subjects will be part of study. A female subject is eligible to participate if she is not pregnant or breastfeeding, and is not a woman of childbearing potential (WOCBP).
  • Additional requirements for pregnancy testing, if needed, during and after study intervention; The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
  • Subject should be capable of giving signed informed consent as which includes compliance with the requirements and restrictions listed in the informed consent form (ICF).

Exclusion Criteria:

  • History or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study intervention; or interfering with the interpretation of data.
  • Abnormal blood pressure as determined by the investigator.
  • Alanine transaminase (ALT) >1.5 times upper limit of normal (ULN).
  • Bilirubin >1.5times ULN (isolated bilirubin >1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
  • Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
  • QT correction using Fridericia Formula (QTcF) >450 millisecond (msec)
  • Past or intended use of over-the-counter or prescription medication (including herbal medications) within 7 days prior to dosing. Paracetamol.
  • History of allergy or sensitivity to DTG.
  • Participation in the study would result in loss of blood or blood products in excess of 500 mL within 56 days.
  • Exposure to more than 4 new chemical entities within 12 months prior to the first dosing day.
  • Current enrollment or past participation within the last 30 days before signing of consent in this or any other clinical study involving an investigational study intervention or any other type of medical research.
  • Presence of Hepatitis B surface antigen (HBsAg), or a positive hepatitis B core antibody with a negative hepatitis B surface antibody at screening.
  • Positive Hepatitis C antibody test result at screening: Subjects with positive Hepatitis C antibody due to prior resolved disease can be enrolled, only if a confirmatory negative Hepatitis C ribonucleic acid (RNA) test is obtained.
  • Positive Hepatitis C RNA test result at screening or within 3 months prior to first dose of study intervention.
  • Positive pre-study drug/alcohol screen.
  • Positive HIV antibody test.
  • Regular use of known drugs of abuse.
  • Regular alcohol consumption within one month prior to the study defined as: For the United Kingdom an average weekly intake of >14 units for males or females. One unit is equivalent to 8 gram (g) of alcohol: a half-pint (~240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.
  • Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products (e.g. nicotine patches or vaporizing devices) within 6 months prior to screening.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03921723


Locations
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United Kingdom
GSK Investigational Site
Nottingham, United Kingdom, NG11 6JS
Sponsors and Collaborators
ViiV Healthcare
Investigators
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Study Director: GSK Clinical Trials ViiV Healthcare

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Responsible Party: ViiV Healthcare
ClinicalTrials.gov Identifier: NCT03921723     History of Changes
Other Study ID Numbers: 209354
First Posted: April 19, 2019    Key Record Dates
Last Update Posted: September 23, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: IPD for this study will be made available via the Clinical Study Data Request site.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints of the study.
Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.
URL: http://clinicalstudydatarequest.com

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by ViiV Healthcare:
Dolutegravir
Human immunodeficiency virus
Sequential study
Dispersible tablet
Suspension
Liquid solution
Additional relevant MeSH terms:
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HIV Infections
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Dolutegravir
Pharmaceutical Solutions
HIV Integrase Inhibitors
Integrase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents