Bioequivalence Study of CRushed TriUMeq With or Without Drip Feed Compared to the Whole Tablet (SCRUM)
Primary Purpose
HIV
Status
Completed
Phase
Phase 1
Locations
Netherlands
Study Type
Interventional
Intervention
Triumeq
Triumeq crushed + breakfast
Triumeq crushed + drip feed
Sponsored by
About this trial
This is an interventional other trial for HIV focused on measuring Triumeq, Pharmacokinetics, Crushing, Drip feed
Eligibility Criteria
Inclusion Criteria:
- Subject is at least 18 and not older than 55 years of age at the day of screening.
- Subject weighs at least 40 kg.
- Subject has a BMI of 18.5-30 kg/m2, extremes included.
- Subject is able and willing to sign the Informed Consent Form prior to screening evaluations.
- Subject is in good age-appropriate health condition as established by medical history, physical examination, electrocardiography, results of biochemistry, haematology and urinalysis testing within four weeks prior to day 1. Results of biochemistry, haematology and urinalysis testing should be within the laboratory's reference ranges (see Appendix A). If laboratory results are not within the reference ranges, the subject is included based on the Investigator's judgment that the observed deviations are not clinically relevant. This should be clearly recorded.
- Subject has a normal blood pressure and pulse rate, according to the Investigator's judgment.
- Subject does not smoke more than 10 cigarettes, 2 cigars, or 2 pipes per day for at least 3 months prior to day 1.
Exclusion Criteria:
- Positive HIV test.
- Positive hepatitis B or C test.
- Positive HLA-B*5701 status (the risk for abacavir hypersensitivity reaction to occur is high for subjects who test positive for the HLA-B*5701 allele).
- Documented history of sensitivity/idiosyncrasy to medicinal products or excipients.
- Relevant history or current condition that might interfere with drug absorption, distribution, metabolism or excretion.
- Inability to understand the nature and extent of the study and the procedures required.
- Pregnant female (as confirmed by an hCG test performed less than 4 weeks before day 1) or breast-feeding female. Female subjects of childbearing potential without adequate contraception, e.g. hysterectomy, bilateral tubal ligation, (non-hormonal) intrauterine device, total abstinence, double barrier methods, or two years post-menopausal. They must agree to take precautions in order to prevent a pregnancy throughout the entire conduct of the study.
- Therapy with any drug (including herbal remedies, multivitamins, magnesium- and calcium-containing supplements, etc.) (for two weeks preceding day 1), except for acetaminophen.
- Relevant history or presence of pulmonary disorders (especially COPD), cardiovascular disorders, neurological disorders (especially seizures and migraine), psychiatric disorders, gastro-intestinal disorders, renal disorders (renal failure determined as an estimated Glomerular Filtration Rate (eGFR) below 50 ml/min (MDRD-based)), hepatic disorders (Child-Pugh B or C), hormonal disorders (especially diabetes mellitus), coagulation disorders.
- History of or current abuse of drugs, alcohol or solvents.
- Gluten free diet.
- Participation in a drug study within 60 days prior to day 1.
- Donation of blood within 60 days prior to day 1.
- Febrile illness within 3 days before day 1.
- Co-worker of Radboud university medical center.
Sites / Locations
- CRCN, Radboud University Medical Center
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Active Comparator
Experimental
Experimental
Arm Label
Triumeq whole
Triumeq crushed + breakfast
Triumeq crushed + drip feed
Arm Description
Single-dose Triumeq as a whole tablet in a fasted state
Single-dose crushed and suspended Triumeq in a fasted state
250 ml drip feed (Nutrison) followed by a single-dose crushed and suspended Triumeq
Outcomes
Primary Outcome Measures
AUC
Secondary Outcome Measures
Adverse events
Full Information
NCT ID
NCT02569346
First Posted
September 30, 2015
Last Updated
December 4, 2020
Sponsor
Radboud University Medical Center
1. Study Identification
Unique Protocol Identification Number
NCT02569346
Brief Title
Bioequivalence Study of CRushed TriUMeq With or Without Drip Feed Compared to the Whole Tablet
Acronym
SCRUM
Official Title
Bioequivalence Study of CRushed TriUMeq With or Without Drip Feed Compared to the Whole Tablet (SCRUM)
Study Type
Interventional
2. Study Status
Record Verification Date
December 2020
Overall Recruitment Status
Completed
Study Start Date
March 2016 (undefined)
Primary Completion Date
May 2016 (Actual)
Study Completion Date
May 2016 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Radboud University Medical Center
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
Dolutegravir is an HIV-1 integrase inhibitor which is marketed as a single tablet (Tivicay®) and in a fixed dose combination tablet with abacavir and lamivudine (Triumeq®, referred to as TRI). For patients with swallowing difficulties, administration of whole tablets can be problematic and tablets are cut or crushed to ease administration.
Currently there is no information about crushing TRI tablets. Therefore this study will be conducted to investigate whether crushed and suspended TRI and crushed and suspended TRI with drip feed are bioequivalent to taking TRI as a whole.
Detailed Description
Dolutegravir is an HIV-1 integrase inhibitor which is marketed as a single tablet (Tivicay®) and in a fixed dose combination tablet with abacavir and lamivudine (Triumeq®, referred to as TRI). For patients with swallowing difficulties, administration of whole tablets can be problematic and tablets are cut or crushed to ease administration. In addition, if HIV patients develop opportunistic infections, patients can become severely ill and may end up on the intensive care. Patients at the intensive care might not be able to swallow medication. Therefore it is useful to know if it is possible to administer TRI through a different route, like a feeding tube. If TRI can be crushed or dissolved and given through a catheter it is also useful to know if it can be given with drip feed.
Currently there is no information about crushing TRI tablets. Depending on the biopharmaceutical characteristics of a drug formulation, crushing tablets can lead to altered pharmacokinetics of drugs. This has been shown for some of the antiretroviral drugs, such as ritonavir, lopinavir, efavirenz and tenofovir.
It is important to know whether pharmacokinetics are influenced by crushing of tablets as low concentrations are associated with virologic failure. Therefore higher doses or switching to other HIV-drugs might be needed. In addition, higher Cmax and/or exposure can lead to toxicity. As a result therapeutic drug monitoring is advised, or crushing the drug is a contra-indication based on the available data.
It has been shown that DTG plasma concentration is influenced by food, with higher AUC en Cmax after a high-fat meal compared to administration in a fasted state. During clinical development, however, dolutegravir intake was studied without regard to food intake. Therefore, it is recommended that dolutegravir can be taken with or without food.
In addition, it has been shown that simultaneous oral ingestion of antacids and dolutegravir gives a decrease in Cmax and AUC of dolutegravir. This interaction is not shown for co-ingestion with omeprazole, which makes it unlikely that this interaction is caused by a pH-lowering effect influencing the absorption of dolutegravir. It is probably a local gastrointestinal complexation phenomenon, similar to what has been observed with other HIV integrase inhibitors. A possible pharmacokinetic interaction between dolutegravir and complexation formers may be expected. Especially considering the active binding sites of dolutegravir which bind magnesium metal ion cofactors. It is currently unclear if certain foods or liquids containing high amounts of magnesium or other cations, like drip feed, can cause this same interaction.
Therefore this study will be conducted to investigate whether crushed and suspended TRI and crushed and suspended TRI with drip feed are bioequivalent to taking TRI as a whole.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
HIV
Keywords
Triumeq, Pharmacokinetics, Crushing, Drip feed
7. Study Design
Primary Purpose
Other
Study Phase
Phase 1
Interventional Study Model
Crossover Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
22 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Triumeq whole
Arm Type
Active Comparator
Arm Description
Single-dose Triumeq as a whole tablet in a fasted state
Arm Title
Triumeq crushed + breakfast
Arm Type
Experimental
Arm Description
Single-dose crushed and suspended Triumeq in a fasted state
Arm Title
Triumeq crushed + drip feed
Arm Type
Experimental
Arm Description
250 ml drip feed (Nutrison) followed by a single-dose crushed and suspended Triumeq
Intervention Type
Drug
Intervention Name(s)
Triumeq
Intervention Description
Single-dose Triumeq as a whole tablet
Intervention Type
Drug
Intervention Name(s)
Triumeq crushed + breakfast
Intervention Description
Single-dose crushed and suspended tablet of Triumeq
Intervention Type
Drug
Intervention Name(s)
Triumeq crushed + drip feed
Intervention Description
Drip feed followed by single-dose crushed and suspended tablet of Triumeq
Primary Outcome Measure Information:
Title
AUC
Time Frame
up to 48 hours after administration
Secondary Outcome Measure Information:
Title
Adverse events
Time Frame
during the entire conduct of the study, 6 weeks in total
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
55 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria:
Subject is at least 18 and not older than 55 years of age at the day of screening.
Subject weighs at least 40 kg.
Subject has a BMI of 18.5-30 kg/m2, extremes included.
Subject is able and willing to sign the Informed Consent Form prior to screening evaluations.
Subject is in good age-appropriate health condition as established by medical history, physical examination, electrocardiography, results of biochemistry, haematology and urinalysis testing within four weeks prior to day 1. Results of biochemistry, haematology and urinalysis testing should be within the laboratory's reference ranges (see Appendix A). If laboratory results are not within the reference ranges, the subject is included based on the Investigator's judgment that the observed deviations are not clinically relevant. This should be clearly recorded.
Subject has a normal blood pressure and pulse rate, according to the Investigator's judgment.
Subject does not smoke more than 10 cigarettes, 2 cigars, or 2 pipes per day for at least 3 months prior to day 1.
Exclusion Criteria:
Positive HIV test.
Positive hepatitis B or C test.
Positive HLA-B*5701 status (the risk for abacavir hypersensitivity reaction to occur is high for subjects who test positive for the HLA-B*5701 allele).
Documented history of sensitivity/idiosyncrasy to medicinal products or excipients.
Relevant history or current condition that might interfere with drug absorption, distribution, metabolism or excretion.
Inability to understand the nature and extent of the study and the procedures required.
Pregnant female (as confirmed by an hCG test performed less than 4 weeks before day 1) or breast-feeding female. Female subjects of childbearing potential without adequate contraception, e.g. hysterectomy, bilateral tubal ligation, (non-hormonal) intrauterine device, total abstinence, double barrier methods, or two years post-menopausal. They must agree to take precautions in order to prevent a pregnancy throughout the entire conduct of the study.
Therapy with any drug (including herbal remedies, multivitamins, magnesium- and calcium-containing supplements, etc.) (for two weeks preceding day 1), except for acetaminophen.
Relevant history or presence of pulmonary disorders (especially COPD), cardiovascular disorders, neurological disorders (especially seizures and migraine), psychiatric disorders, gastro-intestinal disorders, renal disorders (renal failure determined as an estimated Glomerular Filtration Rate (eGFR) below 50 ml/min (MDRD-based)), hepatic disorders (Child-Pugh B or C), hormonal disorders (especially diabetes mellitus), coagulation disorders.
History of or current abuse of drugs, alcohol or solvents.
Gluten free diet.
Participation in a drug study within 60 days prior to day 1.
Donation of blood within 60 days prior to day 1.
Febrile illness within 3 days before day 1.
Co-worker of Radboud university medical center.
Facility Information:
Facility Name
CRCN, Radboud University Medical Center
City
Nijmegen
Country
Netherlands
12. IPD Sharing Statement
Citations:
PubMed Identifier
29796595
Citation
Roskam-Kwint M, Bollen P, Colbers A, Duisenberg-van Essenberg M, Harbers V, Burger D. Crushing of dolutegravir fixed-dose combination tablets increases dolutegravir exposure. J Antimicrob Chemother. 2018 Sep 1;73(9):2430-2434. doi: 10.1093/jac/dky191.
Results Reference
result
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Bioequivalence Study of CRushed TriUMeq With or Without Drip Feed Compared to the Whole Tablet
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