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This is a Phase I, single-center, open label parallel-group, randomized study designed to evaluate the pharmacokinetics (PK), pharmacodynamics (PD, by continuous intragastric pH measurment), safety and tolerability of single and repeated oral doses of linaprazan glurate in 3 different dose levels given once- (QD) or twice daily (BID), for 14 days, with an additional single dose after 2, 4 or 6 days of drug holiday. The population will include healthy male and female subjects.
The subjects will be followed up to 28 days post IMP dosing.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Group 1: 25 mg linaprazan glurate QD | Experimental | 25 mg (one 25 mg oral tablet) linaprazan glurate once daily (QD) for 14 days |
|
| Group 2: 50 mg Linaprazan Glurate QD | Experimental | 50 mg (two 25 mg oral tablets) linaprazan glurate once daily (QD) for 14 days |
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| Group 3: 75 mg Linaprazan Glurate QD | Experimental | 75 mg (three 25 mg oral tablet) linaprazan glurate once daily (QD) for 14 days |
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| Group 4: 25 mg Linaprazan Glurate BID | Experimental | 25 mg (one 25mg oral tablet) linaprazan glurate twice daily (BID) for 14 days |
|
| Group 5: 50 mg Linaprazan Glurate BID | Experimental | 50 mg (two 25 mg oral tablets) linaprazan glurate twice daily (BID) for 14 days |
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| Group 6: 75 mg Linaprazan Glurate BID |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| linaprazan glurate 25 mg QD | Drug | The subjects will receive 25 mg dose in the evening, in a non-fasted condition 30 minutes after the evening meal, for 14 days. Subjects are to follow a standardized food intake schedule. After a drug holiday period of either 2, 4 or 6 days, linaprazan glurate will be given once more in the evening (non-fasted). |
| Measure | Description | Time Frame |
|---|---|---|
| AUC0-24h Linaprazan (QD) | Linaprazan area under the plasma concentration curve, from 0 to 24h post dose on Day 1 and Day 14. QD groups only. | Day 1 and Day 14 |
| AUC0-12, 12-24h Linaprazan (BID) | Linaprazan area under the plasma concentration curve, from 0 to 12h and 12-24h post dose on Day 1 and Day 14. BID groups only. | Day 1 and Day 14 |
| Cmax Linaprazan (QD) | Linaprazan maximum plasma concentration 0-24h post dose for QD groups, at day 1 and day 14. | Day 1 and day 14 |
| Cmax Linaprazan (BID) | Linaprazan maximum plasma concentration 0-12h, and 12-24h post dose for BID groups, at day 1 and day 14. | Day 1 and day 14 |
| AUC0-24h Linaprazan Glurate (QD) | Linaprazan glurate area under the plasma concentration curve, from 0-24h post dose on Day 1 and Day 14. QD groups only. | Day 1 and day 14 |
| AUC0-12h, 12-24h Linaprazan Glurate (BID) | Linaprazan glurate area under the plasma concentration curve, from 0 to 12h and 12-24h post dose on Day 1 and Day 14. BID groups only. | Day 1 and Day 14 |
| Cmax Linaprazan Glurate (QD) | Linaprazan glurate maximum plasma concentration 0-24h post dose for QD groups, at day 1 and day 14. | Day 1 and day 14 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Tanja Turk, M.Pharm | CRS d.o.o Ljubljana, Ukmarjeva Ulica 6, Slovenia, 1000 Contact: Tanja Turk, M.pharm +38651619388 tanja.turk@crs.si | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| CRS d.o.o,Ukmarjeva ulica 6 | Ljubljana | 1000 | Slovenia |
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A total of 132 subjects were screened, of which 75 subjects were randomized, including 2 subjects who did not receive any study medication. Hence 73 subjects were randomized and received at least 1 dose of linaprazan glurate. Three subjects withdrew consent and 3 subjects discontinued due to adverse AEs. A total of 69 subjects completed the study.
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| ID | Title | Description |
|---|---|---|
| FG000 | 25 mg Linaprazan Glurate QD | 25 mg ( one 25 mg oral tablet) Linaprazan Glurate QD for 14 days Linaprazan Glurate 25 mg: The participating subjects will receive 25 mg doses of IMP, QD or BID for 14 days. After a drug holiday period (2, 4 or 6 days), linaprazan glurate will be given once more (QD or BID, on Day 16, 18 or 20). In total, 15 or 30 doses will be given. |
| FG001 | 50 mg Linaprazan Glurate QD | 50 mg (two 25 mg oral tablets) Linaprazan Glurate QD for 14 days Linaprazan Glurate 50 mg: The participating subjects will receive 50 mg doses of IMP, QD or BID for 14 days. After a drug holiday period (2, 4 or 6 days), linaprazan glurate will be given once more (QD or BID, on Day 16, 18 or 20). In total, 15 or 30 doses will be given. |
| FG002 | 75 mg Linaprazan Glurate QD | 75 mg ( three 25 mg oral tablet) Linaprazan Glurate QD for 14 days Linaprazan Glurate 75 mg: The participating subjects will receive 75 mg doses of IMP, QD or BID for 14 days. After a drug holiday period (2, 4 or 6 days), linaprazan glurate will be given once more (QD or BID, on Day 16, 18 or 20). In total, 15 or 30 doses will be given. |
| FG003 | 25 mg Linaprazan Glurate BID | 25 mg ( one 25mg oral tablet) Linaprazan Glurate BID for 14 days Linaprazan Glurate 25 mg: The participating subjects will receive 25 mg doses of IMP, QD or BID for 14 days. After a drug holiday period (2, 4 or 6 days), linaprazan glurate will be given once more (QD or BID, on Day 16, 18 or 20). In total, 15 or 30 doses will be given. |
| FG004 | 50 mg Linaprazan Glurate BID | 50 mg ( two 25 mg oral tablets) Linaprazan Glurate BID for 14 days Linaprazan Glurate 50 mg: The participating subjects will receive 50 mg doses of IMP, QD or BID for 14 days. After a drug holiday period (2, 4 or 6 days), linaprazan glurate will be given once more (QD or BID, on Day 16, 18 or 20). In total, 15 or 30 doses will be given. |
| FG005 | 75 mg Linaprazan Glurate BID | 75 mg ( three 25 mg oral tablet) Linaprazan Glurate BID for 14 days Linaprazan Glurate 75 mg: The participating subjects will receive 75 mg doses of IMP, QD or BID for 14 days. After a drug holiday period (2, 4 or 6 days), linaprazan glurate will be given once more (QD or BID, on Day 16, 18 or 20). In total, 15 or 30 doses will be given. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | 25 mg Linaprazan Glurate QD | 25 mg (one 25 mg oral tablet) linaprazan glurate QD for 14 days |
| BG001 | 50 mg Linaprazan Glurate QD | 50 mg (two 25 mg oral tablets) linaprazan glurate QD for 14 days |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| 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 | AUC0-24h Linaprazan (QD) | Linaprazan area under the plasma concentration curve, from 0 to 24h post dose on Day 1 and Day 14. QD groups only. | Overall # of participants analyzed does not match the participant flow figures due a discrepancy between "completers" and "evaluable" participants (protocol deviations). Figures here represent the number of evaluable subjects. NB! One participant in 50mg QD discontinued before completion of the full study, but only after the primary variables had been collected. Thus this participant's data was evaluable despite being a non-completer. | Posted | Mean | Standard Deviation | nmol/L*h | Day 1 and Day 14 |
|
(S)AE collection was performed on all dosed subjects, in the timeframe between first dose and until safety follow-up 7 +/-2 days after last dose, totalling ca 23-30 days of safety data collection. There was an exception made in the collection timeframe for the SAE, which occurred approximately 2 hours prior to first dose, i.e. outside the actual AE collection time frame as defined by the protocol, but since the event was deemed study procedure related it was reported as an SAE nevertheless.
AEs were coded using MedDRA® Version 25.0. Verbatim terms were coded to lower-level terms within the primary SOC. All AEs reported are MedDRA PTs unless stated otherwise. During the study, the iSRC had 4 meetings to oversee the safety of each subject and all aggregate safety data was reviewed at each meeting.
Number of participants in the All cause mortality and SAE fields below relate to all dosed participants (safety analysis set).
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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 | 25 mg Linaprazan Glurate QD | 25 mg (one 25 mg oral tablet) linaprazan glurate QD for 14 days |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Commotio cerebri | Nervous system disorders | MedDRA (25.0) | Systematic Assessment | not related to the IMP and probably related to the study procedure of blood sampling. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Headache | Nervous system disorders | MedDRA (25.0) | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Cinclus Pharma Holding AB | Cinclus Pharma | +46 8 13 33 10 | gosta.hiller@cincluspharma.com |
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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 | Mar 10, 2023 | Jul 3, 2024 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Oct 4, 2023 | Jul 4, 2024 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D005764 | Gastroesophageal Reflux |
| ID | Term |
|---|---|
| D015154 | Esophageal Motility Disorders |
| D003680 | Deglutition Disorders |
| D004935 | Esophageal Diseases |
| D005767 | Gastrointestinal Diseases |
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| ID | Term |
|---|---|
| C494814 | BID protein, human |
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| Experimental |
75 mg (three 25 mg oral tablet) linaprazan glurate twice daily (BID) for 14 days |
|
|
| linaprazan glurate 50 mg QD | Drug | The subjects will receive 50 mg dose in the evening, in a non-fasted condition 30 minutes after the evening meal, for 14 days. Subjects are to follow a standardized food intake schedule. After a drug holiday period of either 2, 4 or 6 days, linaprazan glurate will be given once more in the evening (non-fasted). |
|
| linaprazan glurate 75 mg QD | Drug | The subjects will receive 75 mg dose in the evening, in a non-fasted condition 30 minutes after the evening meal, for 14 days. Subjects are to follow a standardized food intake schedule. After a drug holiday period of either 2, 4 or 6 days, linaprazan glurate will be given once more in the evening (non-fasted). |
|
| linaprazan glurate 25 mg BID | Drug | The subjects will receive 25 mg dose twice daily, in the morning and in the evening for 14 days. Subjects will be fasted for ≥10 hours overnight before dosing on Day 1 and day 14, until 30 minutes post-dose. During fasting, tap water, but no other drinks, are allowed as desired, except for 1 hour before and 30 minutes after dosing. The second daily dose will be administered 30 minutes after the evening meal, i.e. in a non-fasted condition. The subjects are to follow a standardized food intake schedule. After a drug holiday period of either 2, 4 or 6 days, linaprazan glurate will be given once more (in fasted condition in the morning, non-fasted in the evening). |
|
| linaprazan glurate 50 mg BID | Drug | The subjects will receive 50 mg dose twice daily, in the morning and in the evening for 14 days. Subjects will be fasted for ≥10 hours overnight before dosing on Day 1 and day 14, until 30 minutes post-dose. During fasting, tap water, but no other drinks, are allowed as desired, except for 1 hour before and 30 minutes after dosing. The second daily dose will be administered 30 minutes after the evening meal, i.e. in a non-fasted condition. The subjects are to follow a standardized food intake schedule. After a drug holiday period of either 2, 4 or 6 days, linaprazan glurate will be given once more (in fasted condition in the morning, non-fasted in the evening). |
|
| linaprazan glurate 75 mg BID | Drug | The subjects will receive 75 mg dose twice daily, in the morning and in the evening for 14 days. Subjects will be fasted for ≥10 hours overnight before dosing on Day 1 and day 14, until 30 minutes post-dose. During fasting, tap water, but no other drinks, are allowed as desired, except for 1 hour before and 30 minutes after dosing. The second daily dose will be administered 30 minutes after the evening meal, i.e. in a non-fasted condition. The subjects are to follow a standardized food intake schedule. After a drug holiday period of either 2, 4 or 6 days, linaprazan glurate will be given once more (in fasted condition in the morning, non-fasted in the evening). |
|
| Cmax Linaprazan Glurate (BID) | Linaprazan glurate maximum plasma concentration 0-12h and 12-24h post dose for BID groups, at day 1 and day 14. | Day 1 and day 14 |
| Percentage of Time Gastric pH >4 Over a 24-hour Monitoring Period (Holding Time Ratio, HTR) | Percentage of time gastric pH >4 at Days 1 and 14 over a 24-hour monitoring period following linaprazan glurate administration. Intragastric pH was measured every second with an intragastric probe. The measurements were compressed into 10-minute median intervalls before calculating the % of time with intragastric >pH 4 (HTR). The HTR is presented with descriptive statistics, by dosing group. | Day 1 and day 14 |
| Withdrawal by Subject |
|
| BG002 | 75 mg Linaprazan Glurate QD | 75 mg (three 25 mg oral tablets) linaprazan glurate QD for 14 days |
| BG003 | 25 mg Linaprazan Glurate BID | 25 mg (one 25mg oral tablet) linaprazan glurate BID for 14 days |
| BG004 | 50 mg Linaprazan Glurate BID | 50 mg (two 25 mg oral tablets) linaprazan glurate BID for 14 days |
| BG005 | 75 mg Linaprazan Glurate BID | 75 mg (three 25 mg oral tablets) linaprazan glurate BID for 14 days |
| BG006 | Total | Total of all reporting groups |
| 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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| 50 mg Linaprazan Glurate QD |
50 mg (two 25 mg oral tablets) linaprazan glurate QD for 14 days |
| OG002 | 75 mg Linaprazan Glurate QD | 75 mg (three 25 mg oral tablets) linaprazan glurate QD for 14 days |
|
|
| Primary | AUC0-12, 12-24h Linaprazan (BID) | Linaprazan area under the plasma concentration curve, from 0 to 12h and 12-24h post dose on Day 1 and Day 14. BID groups only. | Posted | Mean | Standard Deviation | nmol/L*h | Day 1 and Day 14 |
|
|
|
| Primary | Cmax Linaprazan (QD) | Linaprazan maximum plasma concentration 0-24h post dose for QD groups, at day 1 and day 14. | Posted | Mean | Standard Deviation | nmol/L | Day 1 and day 14 |
|
|
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| Primary | Cmax Linaprazan (BID) | Linaprazan maximum plasma concentration 0-12h, and 12-24h post dose for BID groups, at day 1 and day 14. | Posted | Mean | Standard Deviation | nmol/L | Day 1 and day 14 |
|
|
|
| Primary | AUC0-24h Linaprazan Glurate (QD) | Linaprazan glurate area under the plasma concentration curve, from 0-24h post dose on Day 1 and Day 14. QD groups only. | Posted | Mean | Standard Deviation | nmol/L*h | Day 1 and day 14 |
|
|
|
| Primary | AUC0-12h, 12-24h Linaprazan Glurate (BID) | Linaprazan glurate area under the plasma concentration curve, from 0 to 12h and 12-24h post dose on Day 1 and Day 14. BID groups only. | Posted | Mean | Standard Deviation | nmol/L*h | Day 1 and Day 14 |
|
|
|
| Primary | Cmax Linaprazan Glurate (QD) | Linaprazan glurate maximum plasma concentration 0-24h post dose for QD groups, at day 1 and day 14. | Posted | Mean | Standard Deviation | nmol/L | Day 1 and day 14 |
|
|
|
| Primary | Cmax Linaprazan Glurate (BID) | Linaprazan glurate maximum plasma concentration 0-12h and 12-24h post dose for BID groups, at day 1 and day 14. | Posted | Mean | Standard Deviation | nmol/L | Day 1 and day 14 |
|
|
|
| Primary | Percentage of Time Gastric pH >4 Over a 24-hour Monitoring Period (Holding Time Ratio, HTR) | Percentage of time gastric pH >4 at Days 1 and 14 over a 24-hour monitoring period following linaprazan glurate administration. Intragastric pH was measured every second with an intragastric probe. The measurements were compressed into 10-minute median intervalls before calculating the % of time with intragastric >pH 4 (HTR). The HTR is presented with descriptive statistics, by dosing group. | PK/PD analysis set (PK/PDAS), a subset of the PK-analysis set, included all pH measurements which were evaluable. 4 subjects were excluded from the PK-analysis set, and thereby also from the PK/PDAS subset, due to study drug incompliance. Another 5 subjects were excluded entirely from the PK/PDAS due to presence of H. pylori (exclusion criteria - could have an impact on acid suppression sensitivity). In total 67 individuals provided at least 1 evaluable pH curve. | Posted | Mean | Standard Deviation | % of time | Day 1 and day 14 |
|
|
|
| 0 |
| 12 |
| 0 |
| 12 |
| 6 |
| 12 |
| EG001 | 50 mg Linaprazan Glurate QD | 50 mg (two 25 mg oral tablets) linaprazan glurate QD for 14 days | 0 | 13 | 0 | 13 | 8 | 13 |
| EG002 | 75 mg Linaprazan Glurate QD | 75 mg (three 25 mg oral tablets) linaprazan glurate QD for 14 days | 0 | 13 | 0 | 13 | 6 | 13 |
| EG003 | 25 mg Linaprazan Glurate BID | 25 mg (one 25mg oral tablet) linaprazan glurate BID for 14 days | 0 | 12 | 0 | 12 | 7 | 12 |
| EG004 | 50 mg Linaprazan Glurate BID | 50 mg ( two 25 mg oral tablets) linaprazan glurate BID for 14 days | 0 | 11 | 0 | 11 | 6 | 11 |
| EG005 | 75 mg Linaprazan Glurate BID | 75 mg (three 25 mg oral tablets) linaprazan glurate BID for 14 days | 0 | 12 | 1 | 12 | 5 | 12 |
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| Syncope | Nervous system disorders | MedDRA (25.0) | Systematic Assessment |
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| Dizziness | Nervous system disorders | MedDRA (25.0) | Systematic Assessment |
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| Seizure | Nervous system disorders | MedDRA (25.0) | Systematic Assessment |
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| fatigue | General disorders | MedDRA (25.0) | Systematic Assessment |
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| Pyrexia | General disorders | MedDRA (25.0) | Systematic Assessment |
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| Malaise | General disorders | MedDRA (25.0) | Systematic Assessment |
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| Cystitis | Infections and infestations | MedDRA (25.0) | Systematic Assessment |
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| nasopharyngitis | Infections and infestations | MedDRA (25.0) | Systematic Assessment |
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| Gastrointestinal infection | Infections and infestations | MedDRA (25.0) | Systematic Assessment |
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| Herpes Simplex | Infections and infestations | MedDRA (25.0) | Systematic Assessment |
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| Urinary Tract infections | Infections and infestations | MedDRA (25.0) | Systematic Assessment |
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| Dysmenorrhoea | Reproductive system and breast disorders | MedDRA (25.0) | Systematic Assessment |
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| menstrual disorder | Reproductive system and breast disorders | MedDRA (25.0) | Systematic Assessment |
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| oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | MedDRA (25.0) | Systematic Assessment |
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| Sinonasal obstruction | Respiratory, thoracic and mediastinal 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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| Back Pain | Musculoskeletal and connective tissue disorders | MedDRA (25.0) | Systematic Assessment |
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| Neck pain | Musculoskeletal and connective tissue disorders | MedDRA (25.0) | Systematic Assessment |
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| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA (25.0) | Systematic Assessment |
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| Haematuria | Renal and urinary disorders | MedDRA (25.0) | Systematic Assessment |
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| Leukocyturia | Renal and urinary disorders | MedDRA (25.0) | Systematic Assessment |
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| Post streptoccocal glumerulonephritis | Renal and urinary disorders | MedDRA (25.0) | Systematic Assessment |
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| proteinuria | Renal and urinary disorders | MedDRA (25.0) | Systematic Assessment |
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| concussion | Injury, poisoning and procedural complications | MedDRA (25.0) | Systematic Assessment |
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| Facial Bones fracture | Injury, poisoning and procedural complications | MedDRA (25.0) | Systematic Assessment |
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| alanine aminotransferase increased | Investigations | MedDRA (25.0) | Systematic Assessment |
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| Aspartate aminotransferase increased | Investigations | MedDRA (25.0) | Systematic Assessment |
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| Pruritus | Skin and subcutaneous tissue disorders | MedDRA (25.0) | Systematic Assessment |
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| arterial puncture | Surgical and medical procedures | MedDRA (25.0) | Systematic Assessment |
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| Phlebitis | Vascular disorders | MedDRA (25.0) | Systematic Assessment |
|
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| D004066 | Digestive System Diseases |
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| AUC0-12h Day 14 |
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| AUC12-24h Day 14 |
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| Cmax 0-12h day 14 |
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| Cmax 12-24h day 14 |
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| AUC0-12h Day 14 |
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| AUC 12-24h Day 14 |
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| Cmax0-12h Day 14 |
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| Cmax 12-24h Day 14 |
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| HTR (%) pH >4 day 14 |
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