MalariaPhase 1NCT05236530
Drug-drug Interaction Study of Ganaplacide and Lumefantrine With Midazolam, Repaglinide, Dextromethorphan, Metformin, Rosuvastatin and Dolutegravir
A Phase 1 study testing Midazolam, Repaglinide and Dextromethorphan in people with Malaria, run by Novartis Pharmaceuticals at 1 site in United Kingdom.
Trial summary
The purpose of this study is to assess the effect of multiple doses of ganaplacide and lumefantrine combination on the substrates of cytochrome P450 (CYP) 3A4 (midazolam), CYP2C8 (repaglinide), CYP2D6 (dextromethorphan), organic cation transporter (OCT) 1, multidrug and toxin extrusion (MATE) 1 (metformin) in Cohort 1… Read more about this study
- Who is it for?
- Ages 18 to 55 yearsHealthy volunteers can take part
- Conditions the study is for
- Malaria
- What is being tested?
- Midazolam, Repaglinide and Dextromethorphan
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 48 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- 9 Mar 2022to 17 Oct 2022
- Phase
- Phase 1
- Are there results?
- None posted in the registry
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 18 to 55 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- Signed informed consent must be obtained prior to participation in the study.
- Healthy male and non-childbearing potential female participants 18 to 55 years of age inclusive, at Screening.
- In good health as determined by medical history, physical examination, vital signs, ECG and clinical laboratory tests at Screening.
- Must weigh at least 50 kg with a body mass index (BMI) within the range of 18.0 to 29.9 kg/m2 inclusive, at Screening.
Who cannot join
- Use of other investigational drugs within 5 half-lives or 30 days prior to first dosing of study treatment, whichever is longer.
- Known family history or presence of long QT syndrome.
- Known history or current clinically significant arrhythmias.
- History or presence of malignancy of any organ system (other than treated localized basal cell or squamous cell carcinoma of the skin or in-situ cervical cancer), treated or untreated, within 5 years of Screening, regardless of whether there is evidence of local recurrence or metastases.
- History or presence of duodenal ulcer, ulcerative colitis or Crohn's disease.
- Presence of active or uncontrolled thyroid disease.
- Has had cholecystectomy (gallbladder removed). Other protocol-defined inclusion/exclusion criteria may apply.
Trial locations and contacts
1 site in 1 country.
United Kingdom1 site
Novartis Investigative Site
Belfast, Northern Ireland, BT9 6AD
About this study
Official title: A Phase I, Open-label, Fixed-sequence, Two-period, Crossover, Drug-drug Interaction Study to Evaluate the Effect of Multiple Doses of Ganaplacide and Lumefantrine Combination on the Pharmacokinetics of Midazolam, Repaglinide, Dextromethorphan, Metformin, Rosuvastatin and Dolutegravir in Healthy Participants
The purpose of this study is to assess the effect of multiple doses of ganaplacide and lumefantrine combination on the substrates of cytochrome P450 (CYP) 3A4 (midazolam), CYP2C8 (repaglinide), CYP2D6 (dextromethorphan), organic cation transporter (OCT) 1, multidrug and toxin extrusion (MATE) 1 (metformin) in Cohort 1 and a substrate of the organic anion transporting polypeptide (OATP) 1B1, OATP1B3 and Breast Cancer Resistance Protein (BCRP) transporter (rosuvastatin) and an antiretroviral drug (dolutegravir) in Cohort 2.
Results from this study will provide guidance on prescribing ganaplacide and lumefantrine combination when co-administered with substrates of the CYP enzymes (CYP3A4, CYP2C8 and CYP2D6) and transporters (OCT1, MATE1, OATP1B1, OATP1B3, and BCRP), and dolutegravir.
Read the detailed description
This is an open-label, 2-cohort, fixed-sequence, 2-period, crossover, drug-drug interaction (DDI) study to evaluate the effect of multiple doses of ganaplacide and lumefantrine combination on the single-dose PK of CYP substrates (midazolam [CYP3A4 substrate], repaglinide [CYP2C8 substrate], dextromethorphan [CYP2D6 substrate]), transporter substrates (metformin [OCT1 and MATE1 substrate] and rosuvastatin [OATP1B1, OATP1B3 and BCRP substrate]) and a human immunodeficiency virus (HIV) integrase inhibitor (dolutegravir) in healthy participants.
For each cohort, the study will consist of a screening period of up to 28 days, Baseline evaluations (on Day -1 of Period 1) and 2 treatment periods which are separated by a washout period. Participants who meet the eligibility criteria at Screening will be admitted to the study site for Baseline evaluations on Day -1 of Period 1. Baseline safety assessments will be performed prior to first dosing of study treatment in Period 1.
Participants will be enrolled in 1 of 2 cohorts only. Cohort 1 Participants enrolled will receive a single oral dose of the 4-probe substrate cocktail consisting of midazolam, repaglinide, dextromethorphan and metformin on Day 1 of Period 1. There will be a washout period of at least 2 days, beginning from the last PK sample collection in Period 1 and continuing until the first dose of study treatment in Period 2. In Period 2, participants will receive ganaplacide and lumefantrine combination orally once daily (q.d.) on Days 1 through 3, with a single oral dose of the 4-probe substrate cocktail co-administered on Day 3. There will be 72 hours of sequential blood sampling for PK assessment of substrates starting after the 4-probe cocktail dosing in each treatment period. Blood samples for ganaplacide, its metabolites and lumefantrine PK will also be collected on Days 1 through 6 of Period 2.
All study treatments will be administered after at least 10 hours of overnight fasting and will be followed by at least 4 hours of post dose fasting.
Cohort 2 Participants enrolled will receive a single oral dose of the 2-probe substrate cocktail consisting of rosuvastatin and dolutegravir on Day 1 of Period 1. There will be a washout period of at least 2 days, beginning from the last PK sample collection in Period 1 and continuing until the first dose of study treatment in Period 2. In Period 2, participants will receive ganaplacide and lumefantrine combination orally q.d. on Days 1 through 3, with a single oral dose of the 2-probe substrate cocktail co-administered on Day 3. There will be 168 hours of sequential blood sampling for PK assessment of substrates starting after the 2-probe cocktail dosing in each treatment period. Blood samples for ganaplacide, its metabolites and lumefantrine PK will also be collected on Days 1 through 10 of Period 2.
All study treatments will be administered after at least 10 hours of overnight fasting and will be followed by at least 4 hours of post dose fasting.
Both Cohorts Safety assessments (including physical examinations, electrocardiograms (ECGs), vital signs, clinical laboratory evaluations [hematology, chemistry, coagulation and urinalysis], pulse oximetry [Cohort 1 only], blood glucose monitoring [Cohort 1 only] and adverse event [AE] and serious adverse event [SAE] monitoring) will be performed during the study.
The Study Completion evaluations will occur on Day 6 of Period 2 for Cohort 1 and on Day 10 of Period 2 for Cohort 2, followed by a post-study safety contact (e.g. follow-up telephone call, email) approximately 30 days after the last dose of study treatment. In the case of early termination, Study Completion evaluations will be conducted prior to discharge from the study.
- Conditions
- Malaria
- Keywords
- Drug-drug interaction, DDI, probe, cocktail, ganaplacide, lumefantrine, midazolam, repaglinide, dextromethorphan, rosuvastatin, metformin, dolutegravir, CYP2C8, CYP2D6, CYP3A4, OATP1B1, MATE1, Pharmacokinetic, PK, safety and tolerability
- Medical subject headings
- Malaria
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MidazolamDrug
Midazolam 2 mg (1 mL of 2 mg/mL oral solution) administered as a single dose in a 4-probe cocktail in the morning in Period 1 on Day 1 and in Period 2 on Day 3.
RepaglinideDrug
Repaglinide 0.5 mg (1 x 0.5 mg tablet) administered as a single dose in a 4-probe cocktail in the morning in Period 1 on Day 1 and in Period 2 on Day 3.
DextromethorphanDrug
Dextromethorphan 15 mg (10 mL of 7.5 mg/5 mL syrup) administered as a single dose in a 4-probe cocktail in the morning in Period 1 on Day 1 and in Period 2 on Day 3.
MetforminDrug
Metformin 500 mg (1 x 500 mg tablet) administered as a single dose in a 4-probe cocktail in the morning in Period 1 on Day 1 and in Period 2 on Day 3.
GanaplacideDrug
Also called KAF156
Ganaplacide 400 mg (4 x 100 mg tablets) administered q.d. in Period 2 on Days 1 - 3, with the 4-probe cocktail co administered on the morning of Day 3.
LumefantrineCombination product
Also called LUM566
Lumefantrine 960 mg (4 x 240 mg sachets) administered q.d. on Days 1 - 3, with the 4-probe cocktail (as a single dose) co administered on the morning of Day 3.
RosuvastatinDrug
Rosuvastatin 5 mg (1 x 5 mg tablet) administered as a single dose in a 2-probe cocktail in the morning in Period 1 on Day 1 and in Period 2 on Day 3.
DolutegravirDrug
Dolutegravir 50 mg (1 x 50 mg tablet) administered as a single dose in a 2-probe cocktail in the morning in Period 1 on Day 1 and in Period 2 on Day 3.
GanaplacideDrug
Also called KAF156
Ganaplacide 400 mg (4 x 100 mg tablets) administered q.d. in Period 2 on Days 1 - 3, with the 2-probe cocktail co administered on the morning of Day 3.
LumefantrineCombination product
Also called LUM566
Lumefantrine 960 mg (4 x 240 mg sachets) administered q.d. on Days 1 - 3, with the 4-probe cocktail (as a single dose) co administered on the morning of Day 3.
| Study group | Role | What they receive |
|---|---|---|
| Cohort 1 | Experimental | Each participant will receive a single oral dose of the 4-probe substrate cocktail consisting of midazolam, repaglinide, dextromethorphan and metformin in the morning of Day 1 of Period 1. In Period 2, participants will receive ganaplacide and lumefantrine combination orally once daily (q.d.) in the morning on Days 1 through 3, with a single oral dose of the 4-probe substrate cocktail co-administered on Day 3. Receives: Drug: Midazolam; Drug: Repaglinide; Drug: Dextromethorphan; Drug: Metformin; Drug: Ganaplacide; Combination Product: Lumefantrine |
| Cohort 2 | Experimental | Each participant will receive a single oral dose of the 2 probe substrate cocktail consisting of rosuvastatin and dolutegravir in the morning on Day 1 of Period 1. In Period 2, participants will receive ganaplacide and lumefantrine combination orally q.d. in the morning on Days 1 through 3, with a single oral dose of the 2 probe substrate cocktail co-administered on Day 3. Receives: Drug: Rosuvastatin; Drug: Dolutegravir; Drug: Ganaplacide; Combination Product: Lumefantrine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Observed maximum plasma concentration (Cmax) for midazolam, repaglinide, dextromethorphan and metformin
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Cmax will be listed and summarized using descriptive statistics.
Measured: 0 (pre-dose) and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post dose.
Area under the serum concentration-time curve from time zero to the time of last quantifiable concentration (AUClast) for midazolam, repaglinide, dextromethorphan and metformin
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. AUClast will be listed and summarized using descriptive statistics.
Measured: 0 (pre-dose) and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post dose.
Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUCinf) for midazolam, repaglinide, dextromethorphan and metformin
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. AUCinf will be listed and summarized using descriptive statistics.
Measured: 0 (pre-dose) and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post dose.
Time of maximum observed drug concentration occurrence (Tmax) for midazolam, repaglinide, dextromethorphan and metformin
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Tmax will be listed and summarized using descriptive statistics.
Measured: 0 (pre-dose) and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post dose.
Apparent total body clearance of drug from plasma following extravascular administration (CL/F) for midazolam, repaglinide, dextromethorphan and metformin
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. CL/F will be listed and summarized using descriptive statistics.
Measured: 0 (pre-dose) and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post dose.
Apparent volume of distribution during terminal elimination phase following extravascular administration (Vz/F) for midazolam, repaglinide, dextromethorphan and metformin
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Vz/F will be listed and summarized using descriptive statistics.
Measured: 0 (pre-dose) and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post dose.
Terminal elimination half-life (T^1/2) for midazolam, repaglinide, dextromethorphan and metformin
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. T^1/2 will be listed and summarized using descriptive statistics.
Measured: 0 (pre-dose) and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post dose.
Observed maximum plasma concentration (Cmax) for rosuvastatin and dolutegravir
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Cmax will be listed and summarized using descriptive statistics.
Measured: 0 (pre dose) and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours post dose.
Area under the serum concentration-time curve from time zero to the time of last quantifiable concentration (AUClast) for rosuvastatin and dolutegravir
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. AUClast will be listed and summarized using descriptive statistics.
Measured: 0 (pre dose) and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours post dose.
Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUCinf) for rosuvastatin and dolutegravir
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. AUCinf will be listed and summarized using descriptive statistics.
Measured: 0 (pre dose) and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours post dose.
Time of maximum observed drug concentration occurrence (Tmax) for rosuvastatin and dolutegravir
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Tmax will be listed and summarized using descriptive statistics.
Measured: 0 (pre dose) and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours post dose.
Apparent total body clearance of drug from plasma following extravascular administration (CL/F) for rosuvastatin and dolutegravir
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. CL/F will be listed and summarized using descriptive statistics.
Measured: 0 (pre dose) and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours post dose.
Apparent volume of distribution during terminal elimination phase following extravascular administration (Vz/F) for rosuvastatin and dolutegravir
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Vz/F will be listed and summarized using descriptive statistics.
Measured: 0 (pre dose) and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours post dose.
Terminal elimination half-life (T^1/2) for rosuvastatin and dolutegravir
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. T^1/2 will be listed and summarized using descriptive statistics.
Measured: 0 (pre dose) and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours post dose.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Feb 2022
- Study start9 Mar 2022
- Primary completion17 Oct 2022
- Study completion17 Oct 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for MalariaStudies of the same condition, open and under way.
- More trials run by Novartis PharmaceuticalsThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
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
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Enrolment
- 48 participants (actual)
Sponsor and investigators
- Lead sponsor
- Novartis Pharmaceuticals
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Medicines for Malaria Venture
- Responsible party
- Sponsor
- Investigators
- Novartis Pharmaceuticals, Study director, Novartis Pharmaceuticals
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05236530
- Sponsor's protocol ID
- CKAF156A2104
- Status last verified
- Nov 2022
- First submitted
- 4 Feb 2022
- Last updated
- 4 Nov 2022
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 4 Nov 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase I, Open-label, Fixed-sequence, Two-period, Crossover, Drug-drug Interaction Study to Evaluate the Effect of Multiple Doses of Ganaplacide and Lumefantrine Combination on the Pharmacokinetics of Midazolam, Repaglinide, Dextromethorphan, Metformin, Rosuvastatin and Dolutegravir in Healthy Participants
- ClinicalTrials.gov ID
- NCT05236530
- Acronym / sponsor ID
- CKAF156A2104
- Conditions
- Malaria
- Keywords
- Drug-drug interaction, DDI, probe, cocktail, ganaplacide, lumefantrine, midazolam, repaglinide
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 48 participants (actual)
- Lead sponsor
- Novartis PharmaceuticalsIndustry (pharma, biotech, devices)
- Collaborators
- Medicines for Malaria Venture
- Study start
- 9 Mar 2022 (actual)
- Primary completion
- 17 Oct 2022 (actual)
- Study completion
- 17 Oct 2022 (actual)
- First posted
- 11 Feb 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of this study is to assess the effect of multiple doses of ganaplacide and lumefantrine combination on the substrates of cytochrome P450 (CYP) 3A4 (midazolam), CYP2C8 (repaglinide), CYP2D6 (dextromethorphan), organic cation transporter (OCT) 1, multidrug and toxin extrusion (MATE) 1 (metformin) in Cohort 1 and a substrate of the organic anion transporting polypeptide (OATP) 1B1, OATP1B3 and Breast Cancer Resistance Protein (BCRP) transporter (rosuvastatin) and an antiretroviral drug (dolutegravir) in Cohort 2.
Results from this study will provide guidance on prescribing ganaplacide and lumefantrine combination when co-administered with substrates of the CYP enzymes (CYP3A4, CYP2C8 and CYP2D6) and transporters (OCT1, MATE1, OATP1B1, OATP1B3, and BCRP), and dolutegravir.
Detailed description
This is an open-label, 2-cohort, fixed-sequence, 2-period, crossover, drug-drug interaction (DDI) study to evaluate the effect of multiple doses of ganaplacide and lumefantrine combination on the single-dose PK of CYP substrates (midazolam [CYP3A4 substrate], repaglinide [CYP2C8 substrate], dextromethorphan [CYP2D6 substrate]), transporter substrates (metformin [OCT1 and MATE1 substrate] and rosuvastatin [OATP1B1, OATP1B3 and BCRP substrate]) and a human immunodeficiency virus (HIV) integrase inhibitor (dolutegravir) in healthy participants.
For each cohort, the study will consist of a screening period of up to 28 days, Baseline evaluations (on Day -1 of Period 1) and 2 treatment periods which are separated by a washout period. Participants who meet the eligibility criteria at Screening will be admitted to the study site for Baseline evaluations on Day -1 of Period 1. Baseline safety assessments will be performed prior to first dosing of study treatment in Period 1.
Participants will be enrolled in 1 of 2 cohorts only. Cohort 1 Participants enrolled will receive a single oral dose of the 4-probe substrate cocktail consisting of midazolam, repaglinide, dextromethorphan and metformin on Day 1 of Period 1. There will be a washout period of at least 2 days, beginning from the last PK sample collection in Period 1 and continuing until the first dose of study treatment in Period 2. In Period 2, participants will receive ganaplacide and lumefantrine combination orally once daily (q.d.) on Days 1 through 3, with a single oral dose of the 4-probe substrate cocktail co-administered on Day 3. There will be 72 hours of sequential blood sampling for PK assessment of substrates starting after the 4-probe cocktail dosing in each treatment period. Blood samples for ganaplacide, its metabolites and lumefantrine PK will also be collected on Days 1 through 6 of Period 2.
All study treatments will be administered after at least 10 hours of overnight fasting and will be followed by at least 4 hours of post dose fasting.
Cohort 2 Participants enrolled will receive a single oral dose of the 2-probe substrate cocktail consisting of rosuvastatin and dolutegravir on Day 1 of Period 1. There will be a washout period of at least 2 days, beginning from the last PK sample collection in Period 1 and continuing until the first dose of study treatment in Period 2. In Period 2, participants will receive ganaplacide and lumefantrine combination orally q.d. on Days 1 through 3, with a single oral dose of the 2-probe substrate cocktail co-administered on Day 3. There will be 168 hours of sequential blood sampling for PK assessment of substrates starting after the 2-probe cocktail dosing in each treatment period. Blood samples for ganaplacide, its metabolites and lumefantrine PK will also be collected on Days 1 through 10 of Period 2.
All study treatments will be administered after at least 10 hours of overnight fasting and will be followed by at least 4 hours of post dose fasting.
Both Cohorts Safety assessments (including physical examinations, electrocardiograms (ECGs), vital signs, clinical laboratory evaluations [hematology, chemistry, coagulation and urinalysis], pulse oximetry [Cohort 1 only], blood glucose monitoring [Cohort 1 only] and adverse event [AE] and serious adverse event [SAE] monitoring) will be performed during the study.
The Study Completion evaluations will occur on Day 6 of Period 2 for Cohort 1 and on Day 10 of Period 2 for Cohort 2, followed by a post-study safety contact (e.g. follow-up telephone call, email) approximately 30 days after the last dose of study treatment. In the case of early termination, Study Completion evaluations will be conducted prior to discharge from the study.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Cohort 1 | Experimental | Drug: Midazolam, Drug: Repaglinide, Drug: Dextromethorphan, Drug: Metformin, Drug: Ganaplacide, Combination Product: LumefantrineEach participant will receive a single oral dose of the 4-probe substrate cocktail consisting of midazolam, repaglinide, dextromethorphan and metformin in the morning of Day 1 of Period 1. In Period 2, participants will receive ganaplacide and lumefantrine combination orally once daily (q.d.) in the morning on Days 1 through 3, with a single oral dose of the 4-probe substrate cocktail co-administered on Day 3. |
| Cohort 2 | Experimental | Drug: Rosuvastatin, Drug: Dolutegravir, Drug: Ganaplacide, Combination Product: LumefantrineEach participant will receive a single oral dose of the 2 probe substrate cocktail consisting of rosuvastatin and dolutegravir in the morning on Day 1 of Period 1. In Period 2, participants will receive ganaplacide and lumefantrine combination orally q.d. in the morning on Days 1 through 3, with a single oral dose of the 2 probe substrate cocktail co-administered on Day 3. |
Who may qualify
- Ages
- 18 to 55 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (4 listed)
- Signed informed consent must be obtained prior to participation in the study.
- Healthy male and non-childbearing potential female participants 18 to 55 years of age inclusive, at Screening.
- In good health as determined by medical history, physical examination, vital signs, ECG and clinical laboratory tests at Screening.
- Must weigh at least 50 kg with a body mass index (BMI) within the range of 18.0 to 29.9 kg/m2 inclusive, at Screening.
Key exclusion criteria (7 listed)
- Use of other investigational drugs within 5 half-lives or 30 days prior to first dosing of study treatment, whichever is longer.
- Known family history or presence of long QT syndrome.
- Known history or current clinically significant arrhythmias.
- History or presence of malignancy of any organ system (other than treated localized basal cell or squamous cell carcinoma of the skin or in-situ cervical cancer), treated or untreated, within 5 years of Screening, regardless of whether there is evidence of local recurrence or metastases.
- History or presence of duodenal ulcer, ulcerative colitis or Crohn's disease.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| MidazolamMidazolam 2 mg (1 mL of 2 mg/mL oral solution) administered as a single dose in a 4-probe cocktail in the morning in Period 1 on Day 1 and in Period 2 on Day 3. | Drug | Cohort 1 |
| RepaglinideRepaglinide 0.5 mg (1 x 0.5 mg tablet) administered as a single dose in a 4-probe cocktail in the morning in Period 1 on Day 1 and in Period 2 on Day 3. | Drug | Cohort 1 |
| DextromethorphanDextromethorphan 15 mg (10 mL of 7.5 mg/5 mL syrup) administered as a single dose in a 4-probe cocktail in the morning in Period 1 on Day 1 and in Period 2 on Day 3. | Drug | Cohort 1 |
| MetforminMetformin 500 mg (1 x 500 mg tablet) administered as a single dose in a 4-probe cocktail in the morning in Period 1 on Day 1 and in Period 2 on Day 3. | Drug | Cohort 1 |
| GanaplacideAlso: KAF156Ganaplacide 400 mg (4 x 100 mg tablets) administered q.d. in Period 2 on Days 1 - 3, with the 4-probe cocktail co administered on the morning of Day 3. | Drug | Cohort 1 |
| LumefantrineAlso: LUM566Lumefantrine 960 mg (4 x 240 mg sachets) administered q.d. on Days 1 - 3, with the 4-probe cocktail (as a single dose) co administered on the morning of Day 3. | Combination product | Cohort 1 |
| RosuvastatinRosuvastatin 5 mg (1 x 5 mg tablet) administered as a single dose in a 2-probe cocktail in the morning in Period 1 on Day 1 and in Period 2 on Day 3. | Drug | Cohort 2 |
| DolutegravirDolutegravir 50 mg (1 x 50 mg tablet) administered as a single dose in a 2-probe cocktail in the morning in Period 1 on Day 1 and in Period 2 on Day 3. | Drug | Cohort 2 |
| GanaplacideAlso: KAF156Ganaplacide 400 mg (4 x 100 mg tablets) administered q.d. in Period 2 on Days 1 - 3, with the 2-probe cocktail co administered on the morning of Day 3. | Drug | Cohort 2 |
| LumefantrineAlso: LUM566Lumefantrine 960 mg (4 x 240 mg sachets) administered q.d. on Days 1 - 3, with the 4-probe cocktail (as a single dose) co administered on the morning of Day 3. | Combination product | Cohort 2 |
Primary outcome
Observed maximum plasma concentration (Cmax) for midazolam, repaglinide, dextromethorphan and metformin
Time frame: 0 (pre-dose) and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post dose.
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Cmax will be listed and summarized using descriptive statistics.
Area under the serum concentration-time curve from time zero to the time of last quantifiable concentration (AUClast) for midazolam, repaglinide, dextromethorphan and metformin
Time frame: 0 (pre-dose) and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post dose.
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. AUClast will be listed and summarized using descriptive statistics.
Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUCinf) for midazolam, repaglinide, dextromethorphan and metformin
Time frame: 0 (pre-dose) and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post dose.
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. AUCinf will be listed and summarized using descriptive statistics.
Time of maximum observed drug concentration occurrence (Tmax) for midazolam, repaglinide, dextromethorphan and metformin
Time frame: 0 (pre-dose) and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post dose.
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Tmax will be listed and summarized using descriptive statistics.
Apparent total body clearance of drug from plasma following extravascular administration (CL/F) for midazolam, repaglinide, dextromethorphan and metformin
Time frame: 0 (pre-dose) and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post dose.
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. CL/F will be listed and summarized using descriptive statistics.
Apparent volume of distribution during terminal elimination phase following extravascular administration (Vz/F) for midazolam, repaglinide, dextromethorphan and metformin
Time frame: 0 (pre-dose) and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post dose.
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Vz/F will be listed and summarized using descriptive statistics.
Terminal elimination half-life (T^1/2) for midazolam, repaglinide, dextromethorphan and metformin
Time frame: 0 (pre-dose) and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post dose.
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. T^1/2 will be listed and summarized using descriptive statistics.
Observed maximum plasma concentration (Cmax) for rosuvastatin and dolutegravir
Time frame: 0 (pre dose) and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours post dose.
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Cmax will be listed and summarized using descriptive statistics.
Area under the serum concentration-time curve from time zero to the time of last quantifiable concentration (AUClast) for rosuvastatin and dolutegravir
Time frame: 0 (pre dose) and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours post dose.
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. AUClast will be listed and summarized using descriptive statistics.
Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUCinf) for rosuvastatin and dolutegravir
Time frame: 0 (pre dose) and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours post dose.
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. AUCinf will be listed and summarized using descriptive statistics.
Time of maximum observed drug concentration occurrence (Tmax) for rosuvastatin and dolutegravir
Time frame: 0 (pre dose) and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours post dose.
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Tmax will be listed and summarized using descriptive statistics.
Apparent total body clearance of drug from plasma following extravascular administration (CL/F) for rosuvastatin and dolutegravir
Time frame: 0 (pre dose) and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours post dose.
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. CL/F will be listed and summarized using descriptive statistics.
Apparent volume of distribution during terminal elimination phase following extravascular administration (Vz/F) for rosuvastatin and dolutegravir
Time frame: 0 (pre dose) and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours post dose.
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Vz/F will be listed and summarized using descriptive statistics.
Terminal elimination half-life (T^1/2) for rosuvastatin and dolutegravir
Time frame: 0 (pre dose) and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours post dose.
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. T^1/2 will be listed and summarized using descriptive statistics.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Nov 2022.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Novartis Pharmaceuticals study director
Novartis Pharmaceuticals
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Midazolam, Repaglinide and Dextromethorphan in people with Malaria, run by Novartis Pharmaceuticals at 1 site in United Kingdom.
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 4 inclusion and 7 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 4 Nov 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. 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 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.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
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?
Observed maximum plasma concentration (Cmax) for midazolam, repaglinide, dextromethorphan and metformin (time frame: 0 (pre-dose) and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post dose.). The study lists 14 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 4 Nov 2022.