EudrCT Number 2012-001531-31 A Phse I, Rndomised, Open-lbel, 3-wy Cross-over Study in Helthy Volunteers to Demonstrte the Bioequivlence of the Nloxegol 25 mg Commercil nd Phse III Formultions nd to Assess the Effect of Food Administrtion on the Phrmcokinetics of the Commercil Formultion Study dtes: First subject enrolled: 03 July 2012 Lst subject lst visit: 11 September 2012 Phse of development: Clinicl phrmcology (I) This study ws performed in complince with Good Clinicl Prctice, including the rchiving of essentil documents.
Publictions None t the time of writing this clinicl study report (CSR). Objectives nd criteri for evlution Tble S1 Objectives nd outcome vribles Objective Outcome Vrible Priority Type Description Description Primry Phrmcokinetic (PK) To demonstrte the bioequivlence between two different film-coted tblet formultions of nloxegol, commercil tblet (test) nd Phse III tblet (reference), fter single-dose dministrtion of 25 mg tblet to helthy volunteers under fsted conditions Secondry PK To ssess the effect of food on the PK of nloxegol commercil film-coted tblets Sfety To investigte sfety nd tolerbility of single orl doses of 25 mg nloxegol dministered s two different tblet formultions in helthy volunteers Explortory Phrmcogenetic To collect nd store DNA for future explortory reserch into genes/genetic vrition tht my influence response (ie, distribution, sfety, tolerbility, nd efficcy) C mx, AUC, t mx, t 1/2 λz, λ z, AUC (0-t), AUC (0-24), CL/F, nd V z /F C mx, AUC, t mx, t 1/2 λz, λ z, AUC (0-t), AUC (0-24), CL/F, nd V z /F Adverse events (AEs), lbortory ssessments, results of physicl exmintion, electrocrdiogrm (ECG), vitl signs (pulse rte nd blood pressure [BP]), nd C-SSRS Not pplicble Sfety To collect plsm smples for sfety biomrker testing tht will llow future ssessment of sfety biomrkers Not pplicble λ z : terminl rte constnt ; AUC: Are under the plsm concentrtion-time curve from zero extrpolted to infinity; AUC (0-t) : Are under the plsm concentrtion-time curve from zero to the time of the lst quntifible concentrtion; AUC (0-24) : Are under the concentrtion-versus-time curve from time 0 to 24 hours postdose; C mx : Mximum observed plsm concentrtion, obtined directly from the observed concentrtion versus time dt; CL/F: Apprent orl clernce from plsm; DNA: Deoxyribonucleic cid; ECG: Electrocrdiogrm; t mx : Time to mximum plsm concentrtion obtined directly from the observed concentrtion versus time dt; t 1/2 λz : Terminl hlf-life; V z /F: Apprent volume of distribution during the terminl phse Results from the explortory nlyses, if performed, would be reported seprtely from the Clinicl Study Report (CSR). 2
Study design This ws single-centre, open-lbel, rndomised, 3-wy cross-over Phse I study in helthy volunteers to demonstrte the bioequivlence of the nloxegol 25 mg film-coted commercil nd Phse III formultions nd to ssess the effect of food on the phrmcokinetics (PK) of the nloxegol commercil formultion. The study comprised of the following visits: Visit 1 (screening; 30 dys of the first dministrtion of the investigtionl product [IP] on Dy 1), Visits 2, 3 nd 4 (tretment period; three rndomised single-dose tretment periods with durtion of 3 dys, ech seprted by wshout period of t lest 7 dys clculted from the time of first dministrtion of nloxegol dose to the next dose dministrtion), nd Visit 5 (follow-up; 7 to 10 dys fter the lst dministrtion of IP). Eligible helthy volunteers were rndomly ssigned to one of the 3 tretments in crossover design in one of the 6 tretment sequences (ABC, BCA, CAB, CBA, ACB, nd BAC)on Dy 1 of Period 1: Tretment A (single orl dministrtion of nloxegol film-coted immedite relese [IR] tblet 25 mg commercil formultion under fsted conditions), Tretment B (single orl dministrtion of nloxogel film-coted IR tblet 25 mg commercil formultion under fed conditions), nd Tretment C (single orl dministrtion of nloxegol film-coted IR tblet 25 mg Phse III formultion under fsted conditions), respectively. Trget subject popultion nd smple size Helthy mle nd femle (non-pregnnt, non-lctting) volunteers ged 18 to 55 yers (inclusive) with body mss index (BMI) between 18 nd 30 kg/m 2 (inclusive) were rndomised in this study. Plnned: Enrolled nd rndomised: Completed: 42 helthy volunteers 42 helthy volunteers 41 helthy volunteers Investigtionl product nd comprtor: dosge, mode of dministrtion nd btch numbers Tble S2 Detils of the investigtionl product Investigtionl product Dosge form nd strength (mode of dministrtion) Mnufcturer Btch number Nloxegol Commercil formultion 25 mg film-coted IR tblet (orl) AstrZenec P Lot: 12-001566AZ F Lot: 12-001279AZ Nloxegol IR: Immedite relese Phse III formultion 25 mg film-coted IR tblet (orl) Phrmceutics Interntionl Incorported (PII) P Lot: WK90884.001 F Lot: 17803.004 3
Durtion of tretment Single IP dministrtion during ech visit (for 3 tretment periods), ech seprted by wshout period of t lest 7 dys (clculted from the time of the first dministrtion of nloxegol dose to the next dose dministrtion). Sttisticl methods A smple size of 34 evluble helthy volunteers provided t lest 90% power to demonstrte tht nloxegol commercil formultion is bioequivlent to the nloxegol Phse III formultion. Assuming dropout rte less thn 19%, 42 helthy volunteers were enrolled. Study conduct, sfety, nd PK dt were summrised using descriptive sttistics, s pproprite. To mke n ssessment of the primry objective of the study, Tretment A (nloxegol commercil formultion under fsted conditions, test) nd Tretment C (nloxegol Phse III formultion under fsted conditions, reference) were compred sttisticlly. Reltive biovilbility in the fsted stte ws estimted using n nlysis of vrince model with the logrithm of AUC nd C mx (primry) s well s AUC (0-t) nd AUC (0-24) (secondry) for nloxegol s the response vrible; tretment, period, nd sequence s fixed effects; nd volunteer within sequence included s rndom effect. If the 90% CI for the geometric LS mens rtios for both AUC nd C mx fell entirely between the prespecified intervl (80.00% to 125.00%), then bioequivlence between the nloxegol commercil formultion nd the Phse III formultion under fsted conditions ws concluded. To mke n ssessment of the effect of food on the nloxegol commercil formultion, the PK prmeters (AUC nd C mx [primry] s well s AUC (0-t) nd AUC (0-24) [secondry]) from the fed rm, Tretment B (test), were compred to tht of the fsted rm, Tretment A (reference). The comprisons were mde using nlysis of vrince model utilising similr methodology s described in the preceding prgrph. Continuous vribles (hemtology, clinicl chemistry, nd vitl signs) were summrised using descriptive sttistics (n, men, stndrd devition [SD], minimum, medin, nd mximum) by tretment group. Ctegoricl vribles were summrised in frequency tbles (frequency nd proportion) by tretment group. Tbultions nd listings of dt for vitl signs nd clinicl lbortory tests re presented. Listings re presented for electrocrdiogrm (ECG) dt nd physicl exmintion results. Results from the Columbi-Suicide Severity Rting Scle (C-SSRS) were presented seprtely in listing only. Subject popultion All 42 helthy volunteers enrolled, were rndomised in the study. All 42 subjects received Tretments A nd B nd 41 subjects received Tretment C. One subject (E0001039), who received Tretments A nd B, ws withdrwn from the study due to positive cotinine test result on dmission to the study centre on Dy -1 nd did not receive Tretment C. The demogrphic nd bseline chrcteristics of ll subjects were in ccordnce with the inclusion/exclusion criteri of the Clinicl Study Protocol (CSP). 4
Summry of phrmcokinetic results Under fsted conditions, nloxegol bsorption ws rpid with pek concentrtions in plsm being chieved within 1 hour post-dose (medin vlue). The men nloxegol plsm concentrtion-time profiles following dministrtion of nloxogel film-coted IR tblet 25 mg commercil formultion (Tretment A) nd nloxegol film-coted IR tblet 25 mg Phse III formultion (Tretment C) in the fsted stte seemed similr. Nloxegol PK prmeters were similr in men vlue between the commercil nd Phse III formultions (Tretments A nd C). Following C mx the decline in nloxegol men plsm concentrtion ws rpid with geometric men t 1/2 λz of 6.99 hours nd 6.55 hours for Tretments A nd C, respectively. The results of the sttisticl comprisons of PK prmeters for tretments A nd C re presented in Tble S3. Tble S3 Sttisticl comprison of primry phrmcokinetic prmeters for tretments A nd C (fsted stte) Prmeter (Units) Tmt Stte n Geo LS men Comprisons 95% CI (%) Pir Rtio (%) 90% CI (%) AUC A Fsted 42 144.6 (126.56, 165.33) A/C 94.38 (89.13, 99.94 ) (ng h/ml) C Fsted 41 153.3 (134.05, 175.22) AUC (0-t) A Fsted 42 142.4 (124.48, 162.80) A/C 93.98 (88.67, 99.60) (ng h/ml) C Fsted 41 151.5 (132.42, 173.28) AUC (0-24) A Fsted 42 140.5 (123.16, 160.20) A/C 93.66 (88.38, 99.25) (ng h/ml) C Fsted 41 150.0 (131.46, 171.10) C mx A Fsted 42 38.35 (33.13, 44.39) A/C 92.38 (82.42, 103.54) (ng/ml) C Fsted 41 41.51 (35.82, 48.10) CI: confidence intervl; Geo: geometric; IR immedite relese; LS lest squres; Tmt: tretment Results bsed on liner mixed effect nlysis of vrince model with terms for sequence, period, nd tretment s fixed effects, nd volunteer within sequence s rndom effect Tretment A: Single orl dministrtion of nloxegol film-coted IR tblet 25 mg commercil formultion (fsted Tretment C: Single orl dministrtion of nloxegol film-coted IR tblet 25 mg Phse III formultion (fsted Under fed conditions (Tretment B), the t mx for the commercil formultion ws prolonged to 2 hours (medin vlue) while men nloxegol plsm concentrtion-time profiles showed higher exposure compred to nloxegol film-coted IR tblet 25 mg commercil formultion dministered in the fsted stte (Tretment A). Nloxegol AUC nd C mx were higher, indicting greter exposure in the presence of food for the commercil formultion. The geometric men t 1/2 λz ws 7.72 hours. The results of sttisticl comprison of primry PK prmeters of the nloxogel commercil formultion in the fed stte (Tretment B) compred to the fsted stte (Tretment A) re shown in Tble S4. 5
Tble S4 Sttisticl comprison of primry phrmcokinetic prmeters for Tretments A nd B (fed versus fsted stte) Prmeters Tmt Stte n Geo LS men Comprisons 95% CI (%) Pir Rtio (%) 90% CI (%) AUC A Fsted 42 144.6 (126.56, 165.33) B/A 145.09 (137.09, 153.56) (ng h/ml) B Fed 42 209.9 (183.62, 239.87) AUC (0-t) A Fsted 42 142.4 (124.48, 162.80) B/A 145.72 (137.56, 154.35) (ng h/ml) B Fed 42 207.4 (181.39, 237.22) AUC (0-24) A Fsted 42 140.5 (123.16, 160.20) B/A 143.60 (135.58, 152.10) (ng h/ml) B Fed 42 201.7 (176.86, 230.05) C mx A Fsted 42 38.35 (33.13, 44.39) B/A 129.51 (115.66, 145.02) (ng/ml) B Fed 42 49.66 (42.90, 57.49) CI: Confidence intervls; Geo: Geometric; IR: Immedite relese; LS: Lest squres; n: Number of observtions; Tmt: Tretment Results bsed on liner mixed effect nlysis of vrince model with terms for sequence, period, nd tretment s fixed effects, nd volunteer within sequence s rndom effect. Tretment A: Single orl dministrtion of nloxegol film-coted IR tblet 25 mg commercil formultion (fsted Tretment B: Single orl dministrtion of nloxegol film-coted IR tblet 25 mg commercil formultion (fed Summry of sfety results There were no deths, serious dverse events (SAEs) or AEs leding to discontinution (DAEs) reported during the study. All the AEs were considered to be mild in severity nd resolved before the end of the study. The number of helthy volunteers with t lest 1 AE ws similr cross ll tretment groups. No cliniclly relevnt chnges were reported in ny lbortory mesurements, vitl signs, ECGs, or physicl exmintion findings. Overll, the IP under study ws considered well tolerted in the popultion studied. 6