NCT ClinialTrials.gov Identifier: sanofi-aventis. Sponsor/company: PRIST_L_ Study Code: PRISTINAMYCIN Date: Generic drug name:

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1 These results are supplied fr infrmatinal purpses nly. Prescribing decisins shuld be made based n the apprved package insert in the cuntry f prescriptin Spnsr/cmpany: sanfi-aventis ClinialTrials.gv Identifier: NCT Study Cde: PRIST_L_01683 Generic drug name: PRISTINAMYCIN Date: 13/Mar/2009 Ratinale f the study: The increasing frequency f Grup A beta-hemlytic Streptcccus (GAS) resistance t macrlides in France called fr new recmmendatins fr the treatment f tnsillitis, ntably in case f cntra-indicatins t beta-lactamins and shrt duratins f treatments must be favured in rder t increase cmpliance. In this cntext sanfi-aventis France cnducted a study in agreement with the French Health Authrities (Afssaps) in rder t dcument the efficacy and safety f pristinamycin in tnsillitis and t prpse an administratin schedule (dse, duratin) fr bth children and adults. Title f the study: Investigatr(s): Study centre(s): Publicatins (reference): A phase III, multicentre, randmized, pen study cmparing the efficacy and safety f pristinamycin 50mg/kg/day in tw daily intakes in children and 1g twice a day in adults fr 4 days versus amxicillin 50mg/kg/day in tw daily intakes in children and 1g twice a day in adults fr 6 days rally, in the treatment f grup A beta-hemlytic streptcccal tnsillitis in patients aged 6 t 25 years. Crdinating Investigatr : Prfessr Jël Gaudelus, Hôpital Verdier, Bndy Planned: 95 GPs and pediatricians Active: 63 GPs and pediatricians Private medical practice all ver France Nt applicable Study perid: Date first patient enrlled: Date last patient cmpleted: Objectives: Methdlgy: 16-OCT MAR-2008 Phase f develpment: III Primary bjective: T demnstrate the nn-inferirity in terms f bacterilgical efficacy f pristinamycin (PRI) administered fr 4 days versus amxicillin (AMX) administered fr 6 days, at the recvery assessment visit V3 (D10/D14), in the treatment f grup A Streptcccus Tnsillitis (GAST) in patients aged 6 t 25, in the per prtcl (PP) ppulatin. Secndary: T cmpare the bacterilgical efficacy f PRI and AMX at visit V3, in the mitt ppulatin. T cmpare the bacterilgical efficacy f PRI and AMX, 3 t 4 weeks after the end f treatment (V4 visit, D25/D34), in the PP and mitt ppulatins. T cmpare the clinical efficacy f PRI and AMX at visits V3 and V4, in the PP and mitt ppulatins. T cmpare the bacterilgical efficacy f PRI and AMX at visits V3 and V4, in the treatment f macrlide resistant GAST, in the PP and mitt ppulatins. T assess the safety f PRI and AMX. Phase III, natinal, prspective, multicentre, cmparative, randmized (2 PRI : 1 AMX), stratified accrding t the patient s age ( 15 years, > 15 years), pen trial, cmparing tw parallel treatment grups, PRI (4 days) versus AMX (6 days) in patients aged 6 t 25, presenting a GAST cnfirmed by a Rapid Diagnstic Test (RDT). Page 1 f 6

2 Number f patients: Planned: 393 (262 in the PRI grup, 131 in the AMX grup), with at least 30 in the PRI grup with a macrlide resistant GAS. Randmized: 395 (260 in the PRI grup, 135 in the AMX grup) Evaluated: PP: in the PRI grup: years, 75 > 15 years 113 in the AMX grup: years, 40 > 15 years mitt: in the PRI grup : years, 86 > 15 years 122 in the AMX grup : years; 45 > 15 years Safety: in the PRI grup: years, 104 > 15 years 134 in the AMX grup: years, 52 > 15 years Diagnsis and criteria fr inclusin: Male and female utpatients. Aged 6 t 25. Bdy weight 20 kg. Suspicin f GAST (erythema and/r pharyngeal exudate and/r tnsil exudate with r-pharyngeal pain and/r dynphagia, fever 38 C, sre satellite adenpathies). Cnfirmed by a psitive RDT. With a thrat swab fr culture. Capable f swallwing a tablet. The written cnsent was t be btained prir t the inclusin int the study, either frm the patients themselves r frm their legal representatives (fr patients less than 18 years ld). Nn inclusin criteria Related t the studied disease Suspicin f viral infectin (assciated dysphnia, cugh, cnjunctivitis r rhinitis). Adenphlegmn, peri-tnsil abscess. Related t the study treatments Knwn r suspected allergy t beta-lactams (penicillin, cephalsprin). Suspicin f infectius mnnuclesis. Phenylketnuria. Cngenital galactsemia, glucse and galactse malabsrbtin syndrme, lactase deficit. Allergy t pristinamycin and/r virginiamycin. Histry f pustular eruptin with pristinamycin. Hypersensitivity r intlerance t gluten. Treatment with cyclsprin, methtrexate, clchicine, allpurinl, tacrlimus, ral anticagulant. Related t previus treatments Patient having been given an antibitic treatment within ne mnth befre inclusin, except fr azithrmycin fr which the minimum wash-ut perid was 3 mnths. Patient n shrt-term crtictherapy. Subjects n stable lng-term crtictherapy initiated prir t the entry int the study culd be included. Related t the patient Breast-feeding wmen. Pregnant wmen r wmen likely t be pregnant. Patient likely t be given, during the study, any frbidden treatment accrding t the prtcl. Treatment with any ther experimental drug during the 4 weeks befre inclusin in the study. Immundeficiency, medically relevant cardivascular, neurlgical, endcrine disrders r any ther relevant disrder making either the realizatin f the prtcl r the interpretatin f the study results difficult. Page 2 f 6

3 Investigatinal prduct: Dse: Administratin: Duratin f treatment: PRI grup: 4 days Reference therapy: Dse: Administratin: Duratin f treatment: AMX grup: 6 days Criteria fr evaluatin: Efficacy Knwn hepatic failure. Knwn renal failure (creatinine clearance < 30 ml/min.) Cancer, hempathies. Histry f drug r alchl abuse. Related t the prtcl Mental cnditin making the patient unable t understand the nature, the bjectives and the likely cnsequences f the study. Patient unable t cmply with the cnstraints f the prtcl (fr instance, nt cperating, unable t attend the fllw-up visits and likely unable t cmplete the study). Subjects deprived f their liberty due t administrative r judicial decisin. Subjects nt benefiting frm the French health and pensins rganizatin. Patient being the investigatr r any member f the study team r related t the investigatr. Pristinamycin 250mg r 500mg tablets. Children: 50mg/kg/day (withut exceeding 2g/day), in tw intakes. Adults: 1 g, twice a day. Oral rute Duratin f bservatin: 1 mnth Amxicillin 500mg capsules r 250mg sachets. Children: 50mg/kg/day (withut exceeding 2g/day), in tw intakes Adults: 1 g, twice a day Oral rute Duratin f bservatin: 1 mnth Primary endpint: Bacterilgical eradicatin rate at V3 visit (D10/D14), in the PP ppulatin Secndary endpint: Bacterilgical eradicatin rate at V3 visit, in the mitt ppulatin Bacterilgical eradicatin rate at V4 visit (D25-D35), in the PP and mitt ppulatins Clinical success rate at visits V3 and V4, in the PP and mitt ppulatins Bacterilgical eradicatin rate at visits V3 and V4 n patients with a macrlide resistant GAST, in the PP and mitt ppulatins Safety: Adverse events reprted by the patient r nted by the investigatr Heart rate, systlic and diastlic bld pressure Page 3 f 6

4 Statistical methds: Summary Study ppulatins: per prtcl (PP), mdified Intentin t Treat (mitt) and safety. Determinatin f sample size : the number f patients was calculated assuming a bacterilgical eradicatin rate at V3 equal t 85% in either grups. Descriptive statistics are given by age stratum, treatment grups and verall. Fr quantitative data cunt, number f missing data, mean, median, minimum and maximum values are prvided. Fr qualitative data cunt, number and percentage f missing data, frequency and percentage are prvided fr each level f the variable. Descriptive statistics f baseline characteristics: demgraphic data, medical and surgical histry, cncmitant diseases, prir and cncmitant medicatins, anamnesis, clinical symptms and clinical signs f tnsillitis. Primary endpint (nn-inferirity analysis): PP ppulatin Tw-sided 95% cnfidence interval in the difference between grups in bacterilgical eradicatin rate at V3 visit. Secndary endpint: Estimatin f the tw-sided 95% cnfidence interval in the difference between grups in the eradicatin rate at V3 in the mitt ppulatin. Estimatin f the tw-sided 95% cnfidence interval in the difference between grups in the eradicatin rate at V4 (mitt and PP). Descriptive statistics f the clinical efficacy at V3 and V4, assessment f crrelatin between clinical and bacterilgical results (mitt and PP ppulatins). Descriptive statistics f the eradicatin rate at V3 and V4 n patients with macrlide resistant GAST (PP and mitt). Descriptive statistics f Safety: Incidence f Treatment Emergent Adverse Events (TEAEs) by treatment grup verall and by system rgan class (MedDRA 9.0). Similar incidences f drug related TEAEs and f serius TEAEs. 395 patients were included and treated ( years, 60.3%).135 were randmized t the AMX grup and 260 t the PRI grup. One patient was lst t fllw-up after visit 1 and therefre excluded frm the safety ppulatin. 42 patients were excluded frm the mitt ppulatin, 13 frm the AMX and 29 frm the PRI grup. In additin t the 42 patients excluded frm the mitt ppulatin, 39 patients were excluded frm the PP ppulatin because f majr prtcl deviatins (9 frm the AMX grup, 30 frm the PRI grup). Bth treatment grups were similar at baseline in terms f predminance f female patients (AMX 56.6%, PRI 53.2%), mean age (AMX 14.1±6.4 years, PRI 13.9±6.1 years), weight (mean values AMX 43.6 kg, PRI 45.8 kg), height (AMX 147 cm, PRI 149 cm) BMI (AMX 19.0 kg/m², PRI 19.5 kg/m²) (PP ppulatin). The tw treatment grups were similar at baseline in terms f disease characteristics. At the time f inclusin, 2.2 days had elapsed n average since the first tnsillitis symptms in the AMX grup, 2.5 days in the PRI grup. A very similar prprtin f patients had a histry f previus episde(s) f tnsillitis, 18.6% in the AMX grup and 17.4% in the PRI grup. On average, the patients had suffered frm 1.3 episdes f tnsillitis in the previus 12 mnths in the AMX grup and 1.5 episdes in the PRI grup. Since the last tnsillitis episde, 6.3 mnths had elapsed in the AMX grup and 6.4 mnths in the PRI grup (PP). The prfile f signs and symptms f tnsillitis was similar in the 2 treatment grups: dynphagia was the mst frequently reprted symptm (AMX 100.0%, PRI 98.5%), fllwed by tnsil/pharyngeal erythema (AMX 98.2%, PRI 99.5%), fever (AMX 94.7%, PRI 94.5%), adenpathies (AMX 93.8%, PRI 92.0%) and pharyngeal exudate (AMX 63.7%, PRI 60.2%)(PP). Similar results were bserved in the mitt analysis set. A ttal f 14 patients did nt cmplete the study (AMX 3: AE 2, investigatr s request 1 and PRI 11: investigatr s request 5, prmter s request 1, lst t fllw-up 1, patient refused t cntinue 2, ther reasn 2). (TEAEs) by treatment grup verall and by system rgan class (MedDRA 9.0). Similar incidences f drug related TEAEs and f serius TEAEs. Page 4 f 6

5 Efficacy results: Primary efficacy criterin The bacterilgical eradicatin rate at V3 in the PP analysis set was 84/201 (41.8%) in the PRI grup and 102/113 (90.3 %) in the AMX grup. The AMX PRI difference in bacterilgical eradicatin rate was 48.5%, 95% CI [40.4%; 56.5%].The upper limit f this 95% CI is greater than 10% and the nn inferirity f PRI cannt be cncluded cmpared t AMX. Secndary efficacy criteria In the mitt ppulatin the bacterilgical eradicatin rate at V3 was 38.5% in the PRI grup and 87.7% in the AMX grup. The difference AMX-PRI was 49.2% with a twsided 95% CI f [41.2%, 57.1%]. In the PP ppulatin, the bacterilgical eradicatin rate at V4 was 36.8% in the PRI grup and 73.5% in the AMX grup. The difference AMX-PRI was 36.6% with tw-sided 95% CI f [26.8%, 46.5%]. The results in the mitt ppulatin were very similar with an eradicatin rate f 33.8% in the PRI grup and 72.1% in the AMX grup. The difference AMX-PRI was 38.4% with a tw-sided 95% CI f [29.0%, 47.8%]. The results btained with pristinamycin may thus be explained by either a lw PRI lcal cncentratin r an insufficient expsitin t PRI in terms f dse and/r duratin f treatment in this specific indicatin that requires the ttal eradicatin f GAS at the end f treatment At V3 in the PP ppulatin, the clinical success (cure r imprvement) rate in the PRI grup (83.6%) was lwer than in the AMX grup (96.5%). This was als the case at V4, with 92.0% f clinical success in the AMX grup vs. 80.6% in the PRI grup. The results in the mitt ppulatin were very similar with a clinical success rate at V3 f 95.1% in the AMX grup and 78.4% in the PRI grup, and 91.0% f clinical success rate at V4 in the AMX grup vs. 75.8% in the PRI grup. Except fr ne patient in the AMX grup, all PP patients with bacterilgical eradicatin at V3 were either clinical cures r imprvements. On the ther hand 7.1% f the patients f the AMX grup and 43.3% f the PRI grup were clinical cures r imprvements but bacterilgical failures. In the mitt ppulatin, 1 bacterilgical success in each treatment grup was a clinical failure (AMX 0.8%, PRI 0.4%) and 8.2% f the patients f the AMX grup and 41.6% f the PRI grup were either clinical cures r imprvements but bacterilgical failures. In the PP analysis set, the eradicatin rate at V3 in patients with macrlide resistant GAST was 8/9 (88.9%) in the AMX grup and 6/11 (54.5%) in the PRI grup. In the mitt analysis set, it was 8/9 (88.9%) in the AMX grup and 6/11 (54.5%) in the PRI. In the PP analysis set, the eradicatin rate at V4 in patients with macrlide resistant GAST was 7/9 (77.8%) in the AMX grup and 4/11 (36.4%) in the PRI grup. In the mitt analysis it was 7/9 (77.8%) in the AMX grup and 4/11 (36.4%) in the PRI grup. Safety results: Sixteen patients frm the AMX grup (11.9%; 15 years 9.8%, > 15 years 15.4%) and 66 frm the PRI grup (25.4%, 15 years 26.3%, > 15 years 24.0%) presented at least ne TEAE. They were 3 (2.2%, 15 years 2.4%, > 15 years 1.9%) in the AMX grup and 32 (12.3%, 15 years 13.5%, > 15 years 10.6%) in the PRI grup with at least ne drug related TEAE. In the AMX grup, ne patient cmplained f diarrhea (> 15 years), ne presented with drug hypersensitivity ( 15 years) and ne with urticaria ( 15 years). In the PRI grup, ne patient suffered frm headache (> 15 years) and 31 (11.9%, 15 years 13.5%, > 15 years 9.6%) cmplained abut gastrintestinal disrders: diarrhea (14, 5.4%, 15 years 6.4%, > 15 years 3.8%), vmiting (9, 3.5%, 15 years 3.8%, > 15 years 2.9%), nausea (5, 1.9%, 15 years 1.3%, > 15 years 2.9%), abdminal pain (4, 1.5%, 15 years 1.3%, > 15 years 1.9%), abdminal upper pain (2, 0.8%, 15 years 1.3%, > 15 years 0.0%). Overall, the safety prfile was similar in children aged 15 r less and in adults. Serius TEAEs were reprted fr 1 patient in the AMX grup (0.7%, > 15 years) and 3 Page 5 f 6

6 (1.2%, 15 years 1.3%, > 15 years 1.0%) in the PRI grup. Nne f the latter was drug related: a mtrbike accident was reprted fr the patient in the AMX grup, a phlegmn f the left tnsil, a right facial palsy and a fall while running fr the 3 patients in the PRI grup. N death ccurred during the study. Tw patients (1.5%, 15 years 2.4%, > 15 years 0.0%) frm the AMX grup permanently withdrew frm the study medicatin due t adverse events (drug related). In the PRI grup they were 10 (3.8%, 15 years 3.8%, > 15 years 3.8%), 8 f them (3.1%, 15 years 3.8%, > 15 years 1.9%) were drug related. Date f reprt: 03-DEC-2008 Page 6 f 6