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This is a phase I, open-label, fixed sequence design, drug-drug-interaction (DDI) study divided in 2 parts. Part I is designed to evaluate whether concomitant treatment with linaprazan glurate and clarithromycin, a strong inhibitor of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein P (PgP), leads to an effect on the systemic exposure to linaprazan glurate and linaprazan and whether there is an effect on the pharmacokinetics of clarithromycin after a single dose of linaprazan glurate. Part II is designed to evaluate the effect of repeated doses of linaprazan glurate on the pharmacokinetics (PK) of a sensitive substrate of CYP3A (midazolam).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| linaprazan glurate | Experimental | Part I: Linaprazan glurate in base form, 100 mg once daily will be administered under fasting conditions at day 1 and day 10. Part II: Linaprazan glurate hydrochloride (HCl), 75 mg twice a day for 13 days. The morning dose will be administered under fasting conditions on Day 2 and Day 14. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Linaprazan glurate | Drug | Investigational Medicinal Product: Linaprazan glurate (tablets). Part I: Linaprazan glurate in base form, 100 mg once daily Day 1 and Day 10. Part II: Linaprazan glurate hydrochloride (HCl), 75 mg twice daily for 13 days. |
| Measure | Description | Time Frame |
|---|---|---|
| Period I, Part I - Linaprazan Glurate and Linaprazan PK Parameters With and Without Co-administration of Clarithromycin - AUC0-inf | Area under the plasma concentration curve from 0 to infinity (AUC0-inf). The AUC were calculated to the time point of the last quantifiable plasma concentration and then extrapolated to infinity using the concentration in the last quantifiable sample and the estimated terminal elimination rate constant (Lambdaz). | Timepoints collected: pre-dose, 15 min, 30 min, 45 min, 1.15 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, 12 h, 18 h, 24 h, 36 h, 48 h and 72 h after dosing (on dosing Days 1 and 10). |
| Period I, Part I - Linaprazan Glurate and Linaprazan PK Parameters With and Without Co-administration of Clarithromycin - AUC0-t | AUC from time 0 to time t (AUC0-t). AUC0-t were analyzed using a mixed model following a natural logarithmic transformation, with fixed effect for treatment and random effect for subject. | Timepoints collected: pre-dose, 15 min, 30 min, 45 min, 1.15 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, 12 h, 18 h, 24 h, 36 h, 48 h and 72 h after dosing (on dosing Days 1 and 10). |
| Period I, Part I - Linaprazan Glurate and Linaprazan PK Parameters With and Without Co-administration of Clarithromycin - Cmax | Maximum plasma concentration (Cmax). Cmax were analyzed using a mixed model following a natural logarithmic transformation, with fixed effect for treatment and random effect for subject. | and 72 h after dosing (on dosing Days 1 and 10). |
| Period II, Part II- Midazolam PK Parameters in the Presence and Absence of Linaprazan Glurate Administration - AUC0-inf | Area under the plasma concentration curve from 0 to infinity - AUCinf. AUC were calculated to the time point of the last quantifiable plasma concentration and then extrapolated to infinity using the concentration in the last quantifiable sample and the estimated terminal elimination rate constant (Lambdaz). | Timepoints collected: Pre-dose, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 12 h, 14 h, 20 h and 24 h (on day 1, 2 and 14). |
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Main Inclusion Criteria:
Main Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Karin Palm | CTC Clinical Trial Consultants AB | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| CTC Clinical Trials Consultants AB | Uppsala | 75237 | Sweden |
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Screening details:
The screening visits were performed within 28 days prior to dosing (Day 28 to Day -1) for both parts.
Part I: 27 subjects were screened and 17 subjects were included in Part I of the study.
Part II: 56 subjects were screened and 18 subjects were included in Part II of the study.
Subjects were recruited from CTC's database of volunteers and from advertising in media (including social media).
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| ID | Title | Description |
|---|---|---|
| FG000 | Period I, Part I | Linaprazan glurate in base form, tablets 100 mg administered under fasting conditions Day 1 and Day 10. Drug drug interaction (DDI) - Clarithromycin (Part I): Index inhibitor (perpetrator drug) Clarithromycin 500 mg twice daily for 9 days (tablets). |
| FG001 | Period II, Part II |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Jan 20, 2023 | Feb 8, 2024 |
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| Drug drug interaction (DDI) - Clarithromycin (Part I) | Drug | Index inhibitor (perpetrator drug) Clarithromycin 500 mg twice daily for 9 days (tablets). |
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| Drug drug interaction (DDI) - Midazolam (Part 2) | Drug | Substrate for CYP3A. Midazolam 2.5 mg once daily (2.5 mL oral solution). |
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| Period II, Part II- Midazolam PK Parameters in the Presence and Absence of Linaprazan Glurate Administration - AUC0-t | AUC from time 0 to time t - AUC0-t. AUC0-t were analyzed using a mixed model following a natural logarithmic transformation, with fixed effect for treatment and random effect for subject. | Timepoints collected: Pre-dose, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 12 h, 14 h, 20 h and 24 h (on day 1, 2 and 14). |
| Period II, Part II- Midazolam PK Parameters in the Presence and Absence of Linaprazan Glurate - Cmax | Maximum plasma concentration - Cmax. Cmax were analyzed using a mixed model following a natural logarithmic transformation, with fixed effect for treatment and random effect for subject. | Timepoints collected: Pre-dose, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 12 h, 14 h, 20 h and 24 h (on day 1, 2 and 14). |
IMP Linaprazan glurate hydrochloride (HCl), tablets 75 mg twice daily for 13 days. Morning dose administered under fasting conditions on Day 2 and Day 14. Drug drug interaction (DDI) - Midazolam: Substrate for CYP3A. Midazolam 2.5 mg once daily (2.5 mL oral solution) Day 1, Day 2 and Day 14. |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | Part I | Linaprazan glurate in base form, tablets 100 mg administered under fasting conditions Day 1 and Day 10. Drug drug interaction (DDI) - Clarithromycin (Part I): Index inhibitor (perpetrator drug) Clarithromycin 500 mg twice daily for 9 days (tablets). |
| BG001 | Part II | IMP Linaprazan glurate hydrochloride (HCl), tablets 75 mg twice daily for 13 days. Morning dose administered under fasting conditions on Day 2 and Day 14. Drug drug interaction (DDI) - Midazolam: Substrate for CYP3A. Midazolam 2.5 mg once daily (2.5 mL oral solution) Day 1, Day 2 and Day 14. |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Period I, Part I - Linaprazan Glurate and Linaprazan PK Parameters With and Without Co-administration of Clarithromycin - AUC0-inf | Area under the plasma concentration curve from 0 to infinity (AUC0-inf). The AUC were calculated to the time point of the last quantifiable plasma concentration and then extrapolated to infinity using the concentration in the last quantifiable sample and the estimated terminal elimination rate constant (Lambdaz). | Data is presented for:
| Posted | Mean | Standard Deviation | h*nmol/L | Timepoints collected: pre-dose, 15 min, 30 min, 45 min, 1.15 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, 12 h, 18 h, 24 h, 36 h, 48 h and 72 h after dosing (on dosing Days 1 and 10). |
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| Primary | Period I, Part I - Linaprazan Glurate and Linaprazan PK Parameters With and Without Co-administration of Clarithromycin - AUC0-t | AUC from time 0 to time t (AUC0-t). AUC0-t were analyzed using a mixed model following a natural logarithmic transformation, with fixed effect for treatment and random effect for subject. | Data is presented for:
| Posted | Mean | Standard Deviation | h*nmol/L | Timepoints collected: pre-dose, 15 min, 30 min, 45 min, 1.15 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, 12 h, 18 h, 24 h, 36 h, 48 h and 72 h after dosing (on dosing Days 1 and 10). |
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| Primary | Period I, Part I - Linaprazan Glurate and Linaprazan PK Parameters With and Without Co-administration of Clarithromycin - Cmax | Maximum plasma concentration (Cmax). Cmax were analyzed using a mixed model following a natural logarithmic transformation, with fixed effect for treatment and random effect for subject. | Data is presented for:
| Posted | Mean | Standard Deviation | nmol/L | and 72 h after dosing (on dosing Days 1 and 10). |
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| Primary | Period II, Part II- Midazolam PK Parameters in the Presence and Absence of Linaprazan Glurate Administration - AUC0-inf | Area under the plasma concentration curve from 0 to infinity - AUCinf. AUC were calculated to the time point of the last quantifiable plasma concentration and then extrapolated to infinity using the concentration in the last quantifiable sample and the estimated terminal elimination rate constant (Lambdaz). | Data is presented for:
| Posted | Mean | Standard Deviation | h*ng/mL | Timepoints collected: Pre-dose, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 12 h, 14 h, 20 h and 24 h (on day 1, 2 and 14). |
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| Primary | Period II, Part II- Midazolam PK Parameters in the Presence and Absence of Linaprazan Glurate Administration - AUC0-t | AUC from time 0 to time t - AUC0-t. AUC0-t were analyzed using a mixed model following a natural logarithmic transformation, with fixed effect for treatment and random effect for subject. | Data is presented for:
| Posted | Mean | Standard Deviation | h*ng/mL | Timepoints collected: Pre-dose, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 12 h, 14 h, 20 h and 24 h (on day 1, 2 and 14). |
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| Primary | Period II, Part II- Midazolam PK Parameters in the Presence and Absence of Linaprazan Glurate - Cmax | Maximum plasma concentration - Cmax. Cmax were analyzed using a mixed model following a natural logarithmic transformation, with fixed effect for treatment and random effect for subject. | Data is presented for:
| Posted | Mean | Standard Deviation | ng/mL | Timepoints collected: Pre-dose, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 12 h, 14 h, 20 h and 24 h (on day 1, 2 and 14). |
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Period I, Part I: AEs (including SAEs) were collected from start of IMP administration (Day 1) until the end-of-study visit on Day 14. Period II, Part II: AEs (including SAEs) were collected from start of IMP administration (Day 1) until the end-of-study visit on Day 22.
The grading of the severity/intensity (grade 1 to grade 5) of AEs followed the common terminology criteria for AEs (CTCAE) v5.0. AEs were assessed as unlikely, possibly, or probably related to the IMPs.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Part I | Linaprazan glurate in base form, tablets 100 mg administered under fasting conditions Day 1 and Day 10. Drug drug interaction (DDI) - Clarithromycin (Part I): Index inhibitor (perpetrator drug) Clarithromycin 500 mg twice daily for 9 days (tablets). | 0 | 17 | 0 | 17 | 11 | 17 |
| EG001 | Part II | IMP Linaprazan glurate hydrochloride (HCl), tablets 75 mg twice daily for 13 days. Morning dose administered under fasting conditions on Day 2 and Day 14. Drug drug interaction (DDI) - Midazolam: Substrate for CYP3A. Midazolam 2.5 mg once daily (2.5 mL oral solution) Day 1, Day 2 and Day 14. | 0 | 18 | 0 | 18 | 8 | 18 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Muscle contusion | Injury, poisoning and procedural complications | MedDRA (25.0) | Systematic Assessment |
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| Dysgeusia | Nervous system disorders | MedDRA (25.0) | Systematic Assessment |
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| Headache | Nervous system disorders | MedDRA (25.0) | Systematic Assessment |
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| Fatigue | General disorders | MedDRA (25.0) | Systematic Assessment |
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| Malaise | General disorders | MedDRA (25.0) | Systematic Assessment |
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| Vessel puncture site bruise | General disorders | MedDRA (25.0) | Systematic Assessment |
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| Abdominal pain upper | Gastrointestinal disorders | MedDRA (25.0) | Systematic Assessment |
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| Abdominal pain | Gastrointestinal disorders | MedDRA (25.0) | Systematic Assessment |
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| Nausea | Gastrointestinal disorders | MedDRA (25.0) | Systematic Assessment |
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| Anal fissure | Gastrointestinal disorders | MedDRA (25.0) | Systematic Assessment |
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| Diarrhoea | Gastrointestinal disorders | MedDRA (25.0) | Systematic Assessment |
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| Faeces soft | Gastrointestinal disorders | MedDRA (25.0) | Systematic Assessment |
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| Flatulence | Gastrointestinal disorders | MedDRA (25.0) | Systematic Assessment |
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| Vomiting | Gastrointestinal disorders | MedDRA (25.0) | Systematic Assessment |
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| Epistaxis | Respiratory, thoracic and mediastinal disorders | MedDRA (25.0) | Systematic Assessment |
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| Rhinorrhoea | Respiratory, thoracic and mediastinal disorders | MedDRA (25.0) | Systematic Assessment |
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| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA (25.0) | Systematic Assessment |
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| Erythema | Skin and subcutaneous tissue disorders | MedDRA (25.0) | Systematic Assessment |
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| Nightmare | Psychiatric disorders | MedDRA (25.0) | Systematic Assessment |
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| Nasopharyngitis | Infections and infestations | MedDRA (25.0) | Systematic Assessment |
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None reported
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Kajsa Larsson, CMO | Cinclus Pharma Holding AB | +46 706750128 | kajsa.larsson@cincluspharma.com |
| Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Mar 6, 2023 | Feb 8, 2024 | SAP_001.pdf |
| ID | Term |
|---|---|
| D004347 | Drug Interactions |
| D016049 | Didanosine |
| D017291 | Clarithromycin |
| D008874 | Midazolam |
| ID | Term |
|---|---|
| D000069437 | Pharmacological Phenomena |
| D002620 | Pharmacological and Toxicological Phenomena |
| D010829 | Physiological Phenomena |
| D007288 | Inosine |
| D011684 | Purine Nucleosides |
| D011687 | Purines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D015224 | Dideoxynucleosides |
| D003853 | Deoxyribonucleosides |
| D009705 | Nucleosides |
| D009706 | Nucleic Acids, Nucleotides, and Nucleosides |
| D012263 | Ribonucleosides |
| D004917 | Erythromycin |
| D018942 | Macrolides |
| D061065 | Polyketides |
| D007783 | Lactones |
| D009930 | Organic Chemicals |
| D001569 | Benzodiazepines |
| D001552 | Benzazepines |
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| Male |
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| Not Hispanic or Latino |
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| Unknown or Not Reported |
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| Asian |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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| Title | Measurements |
|---|---|
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| Linaprazan glurate (co-admin) |
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