| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Healthy voluneers |
| Zdravi prostovoljci |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Not possible to specify |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The objective of this study is to compare the rate and extent of absorption of new formulation of linaprazan glurate 100 mg tablets administered as Treatment A and B in fast conditions versus reference formulation Linaprazan glurate 25x4 mg tablets administered as Treatment C in fed conditions, administered to healthy volunteers in a single-dose, randomized, 3-way cross-over study to evaulate pharmacokinetic effect of food.
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| Cilj te študije je primerjati hitrost in obseg absorpcije nove formulacije 100 mg tablet linaprazanijevega glurata, dane kot zdravljenje A in B v pogojih na tešče, v primerjavi z referenčno formulacijo 25 x 4 mg tablete linaprazanijevega glurata, dane kot obravnave C po visoko kaloričnem obroku z visoko vsebnostjo maščob,na zdravih prostovoljcih v randomizirani, 3-smerni navzkrižni študiji z enim odmerkom za oceno farmakokinetičnega učinka hrane. |
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| E.2.2 | Secondary objectives of the trial |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
For inclusion in the study, subjects must fulfil the following criteria:
1. Willing and able to give written informed consent for participation in the study.
2. Healthy male or female aged 18 to 65 years, inclusive.
3. Body mass index ≥18.5 and ≤35.0 kg/m2.
4. Medically healthy, without abnormal clinically significant medical history, physical findings, vital signs, ECGs, or laboratory values at the time of screening, as judged by the Investigator. Discussion between the Investigator and the Sponsor’s medical representative regarding the clinical relevance of any abnormal laboratory values obtained during the pre-dose period will be encouraged.
5. Prospective subjects, as well as their partners, must agree to the screeninption requirements described in exclusion criteria 1 and 2. Prospective female subjects who are already on a stable regimen of oral, implantable, injectable or transdermal hormonal contraceptives (combined estrogen- and progestogen-containing contraceptives or progestogen-only contraceptives) prior to study enrolment may continue this regimen during the study but must agree to add an additional method of contraception as described in exclusion criterion 1 from 2 weeks prior to the administration of IMP (dosing) until the end-of-study visit.
6. Willing and able to consume the high-fat, high calorie breakfast as described |
Za vključitev v študijo morajo subjekti izpolnjevati naslednje kriterije:
1. Pripravljen in sposoben dati pisno informirano soglasje za sodelovanje v študiji.
2. Zdrav moški ali ženska, stara od 18 do vključno 65 let.
3. Indeks telesne mase ≥18,5 in ≤35,0 kg/m2.
4. Medicinsko zdrav, brez nenormalne klinično pomembne anamneze, fizičnih izvidov, vitalnih znakov, EKG ali laboratorijskih vrednosti v času presejanja, kot je ocenil raziskovalec. Spodbuja se razprava med raziskovalcem in sponzorjevim zdravstvenim predstavnikom glede klinične pomembnosti kakršnih koli nenormalnih laboratorijskih vrednosti, pridobljenih v obdobju pred odmerkom.
5. Potencialne preiskovanke in njihovi partnerji se morajo strinjati z zahtevami glede presejanja, opisanimi v merilih za izključitev 1 in 2. Potencialne preiskovanke, ki so že na stabilnem režimu peroralnih, vsadljivih, injekcijskih ali transdermalnih hormonskih kontraceptivov (kombinirane estrogenske in kontracepcijskimi sredstvi, ki vsebujejo progestogen, ali kontracepcijskimi sredstvi, ki vsebujejo samo progestogen), lahko pred vključitvijo v študijo nadaljujejo s tem režimom med študijo, vendar se morajo strinjati z dodajanjem dodatne metode kontracepcije, kot je opisano v izključitvenem merilu 1, od 2 tednov pred dajanjem IMP (odmerjanje) do ob koncu študija.
6. Pripravljeni in sposobni zaužiti zajtrk z visoko vsebnostjo maščob in visoko kalorij, kot je opisano |
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| E.4 | Principal exclusion criteria |
Subjects will be excluded from the study if any of the following criteria apply:
1. Female subjects of childbearing potential (defined as all subjects physiologically capable of becoming pregnant) unless they agree to use 1 of the suggested highly effective methods of contraception
2. Female subjects of non-childbearing potential who are not required to use contraception
3. Male subjects with a partner of childbearing potential, unless they agree to use 1 of the allowed methods of contraception from 2 weeks prior to dosing until the end-of-study visit:
4. History of any clinically significant disease or disorder which, in the opinion of the Investigator, may either put the subject at risk because of participation in the study, or influence the results or the subject’s ability to participate in the study.
5. History of GERD or clinically significant acid reflux, as judged by the Investigator.
6. History of diabetes, metabolic disorder and/or gastrointestinal disease for which the planned high-fat, high-calorie breakfast might be contraindicated, as judged by the Investigator.
7. Any clinically significant medical/surgical procedure or trauma within 4 weeks of the first administration of IMP, as judged by the Investigator.
8. Malignancy within the past 5 years, with the exception of in situ removal of basal cell carcinoma.
9. Any planned major surgery within the duration of the study (i.e., from screening to end-of-study visit).
10. Subjects who are pregnant, currently breastfeeding, or intend to become pregnant (female subjects) or father a child (male subjects) during the course of the study (i.e., from screening to end-of-study visit).
11. Any positive result on screening for serum hepatitis B surface antigen (not explained by hepatitis B vaccination in the subject’s medical history), hepatitis C antibodies and/or human immunodeficiency virus (HIV).
12. Subjects with swallowing disorders which may affect the subject’s capability to swallow the IMP, as judged by the Investigator.
13. After 10 minutes supine rest at the time of screening, any vital signs outside the following ranges:
o Systolic blood pressure: <90 or ≥140 mmHg
o Diastolic blood pressure <50 or ≥90 mmHg
o Pulse <40 or >90 bpm
14. Prolonged QTcF of >450 ms, cardiac arrhythmias or any clinically significant abnormalities in the resting ECG at the time of screening, as judged by the Investigator.
15. History of severe allergy/hypersensitivity, as judged by the Investigator, or history of hypersensitivity to drugs with a similar chemical structure or class to linaprazan glurate.
16. Use of prohibited medications as detailed in Section 9.6.2.
17. Planned treatment or treatment with another investigational drug within 3 months prior to Day -1. Subjects consented and screened but not dosed in previous Phase I studies will not be excluded.
18. Current smokers or users of nicotine products. Irregular use of nicotine (e.g., smoking, snuffing, chewing tobacco) less than 3 times/week before the screening visit will be allowed.
19. Positive screen for drugs of abuse or alcohol at screening or on admission to the study clinic prior to first administration of the IMP. Positive results that are expected given the subject’s medical history and prescribed medications can be disregarded as judged by the Investigator.
20. History of or current alcohol abuse or excessive intake of alcohol, as judged by the Investigator.
21. History of or current use of drugs of abuse and/or anabolic steroids, as judged by the Investigator.
22. Excessive caffeine consumption defined by a daily intake of > 5 cups (1 cup = approximately 240 mL) of caffeine-containing beverages, as judged by the Investigator.
23. Plasma donation within 1 month of screening or blood donation (or corresponding blood loss) during the last 3 months prior to screening.
24. The Investigator considers the subject unlikely to comply with study procedures, restrictions, and requirements
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Predmeti bodo izključeni iz študije, če velja katero od naslednjih meril:
1. Ženske v rodni dobi (opredeljene kot vse osebe, ki so fiziološko sposobne zanositi), razen če se strinjajo z uporabo ene od predlaganih zelo učinkovitih metod kontracepcije
2. Ženske v nerodni dobi, ki jim ni treba uporabljati kontracepcije
3. Moški subjekti s partnerjem v rodni dobi, razen če se strinjajo z uporabo ene od dovoljenih metod kontracepcije od 2 tednov pred odmerkom do obiska ob koncu študije:
4. Zgodovina katere koli klinično pomembne bolezni ali motnje, ki bi lahko po mnenju raziskovalca subjekta ogrozila zaradi sodelovanja v študiji ali vplivala na rezultate ali sposobnost subjekta, da sodeluje v študiji.
5. Zgodovina GERB ali klinično pomembnega refluksa kisline, po presoji raziskovalca.
6. Anamneza sladkorne bolezni, presnovne motnje in/ali bolezni prebavil, za katere bi lahko bil po presoji raziskovalca kontraindiciran načrtovani visokokalorični zajtrk z visoko vsebnostjo maščob.
7. Vsak klinično pomemben medicinski/kirurški poseg ali travma v 4 tednih po prvem dajanju IMP po presoji raziskovalca.
8. Malignost v zadnjih 5 letih, z izjemo in situ odstranitve bazalnoceličnega karcinoma.
9. Vse načrtovane večje operacije v času trajanja študije (tj. od presejanja do obiska ob koncu študije).
10. Subjekti, ki so noseči, trenutno dojijo ali nameravajo zanositi (ženski subjekti) ali sploditi otroka (moški subjekti) med potekom študije (tj. od presejanja do obiska ob koncu študije).
11. Kakršen koli pozitiven rezultat presejalnega pregleda za serumski površinski antigen hepatitisa B (ki ni pojasnjen s cepljenjem proti hepatitisu B v anamnezi subjekta), protitelesa proti hepatitisu C in/ali virus humane imunske pomanjkljivosti (HIV).
12. Subjekti z motnjami požiranja, ki lahko vplivajo na sposobnost subjekta, da pogoltne IMP, kot presodi raziskovalec.
13. Po 10 minutah ležečega počitka v času presejanja kateri koli vitalni znaki zunaj naslednjih razponov:
o Sistolični krvni tlak: <90 ali ≥140 mmHg
o Diastolični krvni tlak <50 ali ≥90 mmHg
o Utrip <40 ali >90 utripov na minuto
14. Podaljšan QTcF >450 ms, srčne aritmije ali kakršne koli klinično pomembne nepravilnosti v EKG v mirovanju v času presejanja, kot je ocenil raziskovalec.
15. Anamneza hude alergije/preobčutljivosti po presoji raziskovalca ali anamneza preobčutljivosti na zdravila s podobno kemijsko strukturo ali razredom kot linaprazan glurat.
16. Uporaba prepovedanih zdravil, kot je podrobno opisano v razdelku 9.6.2.
17. Načrtovano zdravljenje ali zdravljenje z drugim zdravilom v preskušanju v 3 mesecih pred dnevom -1. Preiskovanci, ki so privolili in so bili pregledani, vendar niso prejeli odmerka v prejšnjih študijah I. faze, ne bodo izključeni.
18. Trenutni kadilci ali uporabniki nikotinskih izdelkov. Nepravilna uporaba nikotina (npr. kajenje, njuhanje, žvečenje tobaka) manj kot 3-krat na teden pred presejalnim obiskom bo dovoljena.
19. Pozitiven test za zlorabo drog ali alkohola ob presejalnem pregledu ali ob sprejemu v študijsko kliniko pred prvim dajanjem IMP. Pozitivni rezultati, ki so pričakovani glede na preiskovančevo anamnezo in predpisana zdravila, se lahko po presoji raziskovalca ne upoštevajo.
20. Preteklost ali trenutna zloraba alkohola ali prekomerno uživanje alkohola, po presoji preiskovalca.
21. Zgodovina ali trenutna uporaba drog in/ali anaboličnih steroidov po presoji preiskovalca.
22. Prekomerno uživanje kofeina, opredeljeno z dnevnim vnosom > 5 skodelic (1 skodelica = približno 240 ml) pijač, ki vsebujejo kofein, po presoji preiskovalca.
23. Darovanje plazme v enem mesecu po presejalnem pregledu ali krvodajalstvo (ali ustrezna izguba krvi) v zadnjih 3 mesecih pred presejalnim pregledom.
24. Raziskovalec meni, da subjekt verjetno ne bo upošteval študijskih postopkov, omejitev in zahtev |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Endpoints
Primary endpoints
o Area under the plasma concentration vs. time curve (AUC) from time 0 to infinity (AUCinf)
o AUC from time 0 to the last measurable concentration (AUClast)
o Maximum plasma concentration (Cmax)
Secondary endpoints (PK)
o Time to Cmax (Tmax)
o Delay between the time of dosing and the time of appearance of plasma concentration (Tlag)
o Terminal elimination half-life (T1/2)
o AUC percent extrapolation (AUCextrapol%)
o Apparent clearance (CL/F)
o Apparent volume of distribution (Vz/F) Secondary endpoints (safety)
• Frequency, seriousness, and intensity of adverse events (AEs).
• Clinically significant changes in ECG, vital signs, safety laboratory measurements (clinical chemistry/hematology/coagulation) and physical examination findings.
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Območje pod krivuljo koncentracijo v plazmi v
primerjavo s časovno krivulja (AUC) od časa 0 do neskončnosti (AUC inf )
o AUC od časa 0 do zadnje merljive koncentracije (AUC last )
o Največja koncentracija v plazmi (C max )
Relativna biološka uporabnost linaprazana po obroku s hrano v primerjavi s stanjem na
tešče na podlagi razmerij povprečja za AUC inf , AUC last in C max .
Sekundarne končne točke (PK)
Relativna biološka uporabnost linaprazan glurata za testno formulacijo v primerjsavi z
referenčno formulacijo linaprazan glurata, ki temelji na razmerjih povprečja za AUC inf ,
AUC last in C max .
Relativna biološka uporabnost linaprazanijevega glurata v pogojih hranjenja v
primerjavi s pogoji brez hranjenja, na podlagi sredin povprečij za AUC inf , AUC last in
C max .
o Čas za C max (T max )
o Zamik med časom odmerjanja in časom pojava koncentracije v plazmi. (T lag )
o Končni razpolovni čas izločanja (T1/2)
o AUC odstotna ekstrapolacija (AUC extrapol% )
o Navidezni očistek (CL/F)
o Navidezni volume porazdelitve (V z /F) |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
There will be total of 17 Blood samples collected for the analysis including pre-dose at -01:00 and at 00:15, 00:30, 01:00, 01:30, 02:00, 03:00, 04:00, 06:00, 08:00, 12:00, 14:00, 20:00, 24:00, 36:000, 48:00 and 72:00 hh:mm post-dose.
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Vzorci krvi za farmakokinetiko bodo odvzeti pred odmerkom (v -01:00 ur:min pred
odmerjanjem) in ob 00:15, 00:30, 01:00, 01:30, 02:00, 03:00, 04: 00.00, 6.00, 8.00, 12.00, 14.00,
20.00, 24.00, 36.00, 48.00 in 72.00 ur po odmerku (1x3ml vsak) |
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| E.5.2 | Secondary end point(s) |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Comparative study of bioavailability |
| Primerjalna študija biološke uporabnosti |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| bioavailability |
| študija biološke uporabnosti |
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| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | |
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