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Treatment of Acute Otitis Media With Azithromycin. Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development. Azithromycin for Acute Otitis Media Rationale. Bactericidal against the pathogens responsible for AOM.

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Treatment of acute otitis media with azithromycin l.jpg

Treatment of Acute Otitis Media With Azithromycin

Michael Dunne, MD

Vice President

Clinical Development, Infectious Diseases

Pfizer Global Research and Development


Azithromycin for acute otitis media rationale l.jpg
Azithromycin for Acute Otitis MediaRationale

  • Bactericidal against the pathogens responsible for AOM


Azithromycin for acute otitis media rationale3 l.jpg
Azithromycin for Acute Otitis MediaRationale

  • Bactericidal against the pathogens responsible for AOM

  • Pharmacokinetic profile suited for treatment of infection

    • Reaches effective concentrations in middle ear

    • Sustained concentrations in white blood cells

    • Complete course of therapy in single dose

    • Optimizes compliance


Azithromycin for acute otitis media rationale4 l.jpg
Azithromycin for Acute Otitis MediaRationale

  • Bactericidal against the pathogens responsible for AOM

  • Pharmacokinetic profile suited for treatment of infection

    • Reaches effective concentrations in middle ear

    • Sustained concentrations in white blood cells

    • Complete course of therapy in single dose

    • Optimizes compliance

  • Well tolerated, safe antibiotic

    • Recommended in penicillin allergic patients

    • Over 40 million prescriptions for oral suspension


Azithromycin for acute otitis media rationale5 l.jpg
Azithromycin for Acute Otitis MediaRationale

  • Bactericidal against the pathogens responsible for AOM

  • Pharmacokinetic profile suited for treatment of infection

    • Reaches effective concentrations in middle ear

    • Sustained concentrations in white blood cells

    • Complete course of therapy in single dose

    • Optimizes compliance

  • Well tolerated, safe antibiotic

    • Recommended in penicillin allergic patients

    • Over 40 million prescriptions for oral suspension

  • Clinical efficacy equivalent to approved therapies

    • Originally established in five day regimen

    • Extended to shorter regimens of three day and single dosing


Advantages of single dose azithromycin l.jpg
Advantages of Single Dose Azithromycin

  • Provides best drug levels early in course of infection

  • Takes advantage of important host defenses

    • Maximal neutrophil recruitment optimizes azithromycin delivery

    • Febrile response increases azithromycin uptake1

  • Maximizes rate of compliance

  • Minimizes burden on caregiver

1Fietta, et al., J.Chemotherapy 1997


Azithromycin for acute otitis media l.jpg
Azithromycin for Acute Otitis Media

  • Chemistry/Pharmacokinetics

  • Microbiology

  • Clinical Data

  • Conclusion


Azithromycin the first azalide antibiotic l.jpg

H3C

CH3

CH3

N

HO

H3C

N

OH

H3

C

CH3

HO

CH3

O

O

CH3

HO

O

H3

C

CH3

O

O

OH

CH3

CH3

O

CH3

H3

C

O

Azithromycin

Azithromycin: The First Azalide Antibiotic


Azithromycin uptake by white blood cells l.jpg

Acid Vesicle pH 5.0 A

A

A

AH+

AH+

AH+

Extracellular Blood, pH 7.4

Cytoplasm pH 7.2

AzithromycinUptake by White Blood Cells


Acute otitis media histopathology l.jpg
Acute Otitis MediaHistopathology

S. Giebink, M.D., FDA AC presentation, November 1997


Azithromycin serum and middle ear fluid levels in children l.jpg
AzithromycinSerum and Middle Ear Fluid Levels in Children

*Cells / middle ear fluid


Azithromycin for acute otitis media12 l.jpg
Azithromycin for Acute Otitis Media

  • Chemistry/Pharmacokinetics

  • Microbiology

  • Clinical Data

  • Conclusion


Azithromycin in vitro activity l.jpg
Azithromycin: In Vitro Activity

Hoban. CID 2001


Azithromycin in vitro activity14 l.jpg
Azithromycin: In Vitro Activity

aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000


Antimicrobial resistance to s pneumoniae according to penicillin susceptibility 1998 l.jpg
Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998

Whitney. NEJM 2000


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Antimicrobial Susceptibility of S. pneumoniaeby Age Group

% Susceptible

Thornsberry AAC 1999


Susceptibility of s pneumoniae to macrolides and penicillin in the u s from surveillance studies l.jpg
Susceptibility of S. pneumoniae to Macrolidesand Penicillin in the U.S. From Surveillance Studies

% Resistant

Year


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AzithromycinBactericidal Activity Against Streptococcus pneumoniae*

Log10 CFU/ml

Time (hours)

*MIC =0.06 g/ml


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AzithromycinBactericidal Activity Against Haemophilus influenzae*

Log10 CFU/ml

Time (hours)

*MIC =0.78 g/ml


Azithromycin chinchilla model of aom due to h influenzae l.jpg
AzithromycinChinchilla Model of AOM due to H. influenzae

Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS

Day 0: Otomicroscopic exam of TM and tympanometry

Culture middle ear fluid (MEF)

Initiate therapy via orogastric feeding tube

Day 3: Otomicroscopic exam and tympanometry

Culture and collect MEF and serum

Continue therapy

Day 5: Otomicroscopic exam and tympanometry

Culture and collect MEF

Complete therapy

Day 7-10: Repeat exams; Culture and collect MEF

Babl. 40th ICAAC 2000


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AzithromycinChinchilla Middle Ear Fluid Concentrations

Azithromycin (mg/ml)

Azithromycin Therapy

Day

Total MEF = frozen/thawed middle ear fluid

Babl. 40th ICAAC 2000


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AzithromycinChinchilla Model of AOM due to H. influenzae

MEDIAN CFU FOR NTHI BY TREATMENT GROUP

Log scale CFU

Day

* Sterile ears with <10CFU

Azithromycin therapy

Babl. 40th ICAAC 2000


Azithromycin chinchilla model of aom due to h influenzae23 l.jpg
AzithromycinChinchilla Model of AOM due to H. influenzae

Percent Culture Positive

Day

Babl. 40th ICAAC 2000


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Azithromycin for Acute Otitis Media

  • Chemistry/Pharmacokinetics

  • Microbiology

  • Clinical Program

    • Overview of Five Day Program

    • Single Dose

    • Three Day Dosing

    • Focus on Selected Topics

  • Conclusion


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Azithromycin 5 Day ProgramClinical Outcome at Day 30*

Per Protocol

Study

Outcome

Azithromycin

Amox/Clav

Cure

181/264 (69%)

168/257 (65%)

134

176

Cure

75/122 (61%)

--

Cure

36/45 (80%)

27/35 (77%)

128

*Medical officers assessment; no ITT analysis done


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Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30


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Azithromycin 5 Day Program Treatment Related Adverse Events*

Azithromycin

Amox/Clav

N

(%)

N

(%)

No. Patients

975

827

No. Patients with Treatment-Related AEs

70

(7.2)

190

(23.0)

No. with Common Adverse Events

Diarrhea

17

(1.7)

104

(12.6)

Vomiting

17

(1.7)

34

(4.1)

Abdominal Pain

14

(1.4)

19

(2.3)

*Protocols 128,134,178,322,334,337; Amox/Clav comparative studies


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Azithromycin for Acute Otitis Media

  • Chemistry/Pharmacokinetics

  • Microbiology

  • Clinical Program

    • Overview of Five Day Program

    • Single Dose

    • Three Day Dosing

    • Focus on Selected Topics

  • Conclusion


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Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media

  • Five Day Dosing

    • 30 mg/kg: 10 mg/kg then 5,5,5,5

    • Approved in United States in 1995

  • Three Day Dosing

    • 30 mg/kg: 10 mg/kg qd X 3

    • Approved in Europe in 1990

  • Single Dose Therapy

    • 30 mg/kg: given as single dose


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1998 FDA GuidanceAcute Otitis Media

“Clinical-only” Trial

  • One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized

    • Test-of-Cure visit (2 - 4 weeks from initiation of therapy)

      Clinical/Microbiologic Trial

  • One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug

  • For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates


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Azithromycin Overview of Single Dose and Three Day Programs

Pivotal Studies

  • Single dose program

    R-0581: double-blind, randomized, comparative clinical trial

    1015: open, noncomparative, microbiology study

  • Three day dosing

    1014: double-blind, randomized, comparative clinical trial

    Supportive Study

    95-001: randomized comparative single center study

    • Baseline tympanocentesis performed

    • Compares three day dosing with single dose therapy with ceftriaxone


Single dose program l.jpg

Single Dose Program

Phase 2 Study 95-001

Phase 3 Study R-0581 Study 1015


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Single Dose ProgramInclusion Criteria: Symptoms

1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever

2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance)


Single dose program inclusion criteria signs of tympanic membrane disease l.jpg
Single Dose ProgramInclusion Criteria: Signs of Tympanic Membrane Disease

1 Any one of these findings

2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level


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Single Dose ProgramKey Exclusion Criteria

Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg


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Single Dose ProgramStatistical Methods

  • Primary Endpoint: Clinical Cure

  • Primary Timepoint (Test of Cure): Day 28

    • Cure

    • Failure

    • Improvement (R-0581 and 95-001)


Single dose program statistical methods37 l.jpg
Single Dose ProgramStatistical Methods

  • Clinical Efficacy Population

    • At least one dose of study medication

    • Diagnosis of AOM at baseline

    • Analyzed at Day 28

      • Return for visit at Day 28

      • Concomitant antibiotic for failure counts as failure

  • Bacteriological Efficacy Population

    • Positive baseline culture for at least one relevant pathogen


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Single Dose Program Definition of Cure



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Study 95-001 Methods

  • Objectives

    • Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media

  • Design

    • Prospective

    • Single-center in Costa Rica

    • Performed in 1995-1997


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Study 95-001 Experimental Design

*Baseline tympanocentesis


Study 95 001 patient disposition l.jpg
Study 95-001Patient Disposition


Study 95 001 demographics l.jpg
Study 95-001Demographics

Azithromycin

Ceftriaxone

Single Dose

N = 66

Three Day

N = 66

N = 66

Age:

< 2 Yrs

26 (39%)

26 (39%)

35 (53%)

2 Yrs - 12 Yrs

40 (61%)

40 (61%)

31 (47%)

Mean Age (Yrs, ±SD)

2.5 (+ 1.3)

2.7 (+ 1.5)

2.3 (+ 1.4)

% Male

56%

55%

48%

Race:

White

97%

95%

98%

Black

2%

2%

0%

Hispanic

2%

3%

2%


Study 95 001 results l.jpg
Study 95-001Results


Study 95 001 clinical efficacy population l.jpg
Study 95-001 Clinical Efficacy Population

1 Day (%)

Azithromycin

3 Day (%)

Ceftriaxone

(%)

95% CI1 [%]

Randomized Patients

66

66

66

Day 14

64

63

62

Success

62 (97)

60 (95)

61 (98)

[-8,5]

Cure

26

18

21

Improvement

36

42

40

Failure

2 (3)

3 (5)

1 (2)

Day 28

65

66

64

Success

61 (94)

61 (92)

62 (97)

[-12,6]

Cure

56 (86)

51 (77)

49 (77)

[- 5, 25]

Improvement

5

10

13

Failure

4 (6)

5 (8)

2 (3)

1 95% CI for (single dose azithromycin – comparator)


Study 95 001 clinical outcome at day 28 by age l.jpg
Study 95-001 Clinical Outcome at Day 28 by Age

1 Day (%)

3 Day (%)

Ceftriaxone (%)

Azithromycin

< 2 years of age

25

27

33

Cure

19 (76)

18 (67)

23 (70)

Failure

6 (24)

9 (33)

10 (30)

> 2 years of age

40

39

31

Cure

37 (93)

33 (85)

26 (84)

Failure

3 (8)

6 (15)

5 (16)


Study 95 001 susceptibility l.jpg
Study 95-001 Susceptibility

  • S. pneumoniae susceptibility (N=57)

    • Azithromycin

      • 46 susceptible

      • 11 resistant (MIC > 0.5 mg/ml)

    • Ceftriaxone

      • All isolates were susceptible to ceftriaxone

  • All H. influenzae and M. catarrhalis were susceptible to azithromycin and ceftriaxone


Study 95 001 clinical cure per baseline pathogen at day 28 l.jpg
Study 95-001 Clinical Cure Per Baseline Pathogen at Day 28


Study 95 001 treatment related adverse events l.jpg
Study 95-001 Treatment Related Adverse Events*

Azithromycin

1 Day

3 Day

Ceftriaxone

Patients Treated

66

66

66

Discontinued

0 (0)

0 (0)

0 (0)

Patients w/ AE

7 (11)

6 (9)

6 (9)

Diarrhea

2 (3)

3 (5)

4 (6)

Rash

1 (2)

0 (0)

4 (6)

0 (0)

Vomiting

3 (5)

0 (0)

*2 or more events on any treatment regimen


Study r 0581 l.jpg

Study R-0581

Single Dose Therapy


Study r 058151 l.jpg
Study R-0581

  • Objective

    • Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM

  • Design

    • Multicenter, randomized

      • All sites in the United States

    • Double blind, double dummy

      • Azithromycin: 30 mg/kg single oral dose

      • Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days

      • Matching placebo for each active study drug


Study r 0581 visits and assessments l.jpg
Study R-0581 Visits and Assessments

*Patients who vomited within 30 minutes were redosed

1 Including parental questionnaire


Study r 0581 patient disposition l.jpg
Study R-0581Patient Disposition


Study r 0581 demographics l.jpg
Study R-0581Demographics



Study r 0581 clinical outcome l.jpg
Study R-0581 Clinical Outcome

Azithromycin (%)

Amox/Clav (%)

95% CI1[%]

Number of Patients

173

173

Day 14

160

161

Success

139 (87)

142 (88)

[-9, 7]

Cure

105

121

Improvement

34

21

Failure

21 (13)

19 (12)

Day 28

151

154

Success

114 (75)

116 (75)

[-10, 11]

Cure

112 (74)

108 (70)

[-7, 15]

Improvement

2

8

Failure

37 (25)

38 (25)

1 95% CI for (azithromycin – comparator)


Study r 0581 clinical outcome at day 28 by age l.jpg
Study R-0581 Clinical Outcome at Day 28 by Age

95% CI1[%]

Azithromycin

Amox/Clav

N (%)

N (%)

< 2 years of age

64

53

Cure

40 (63)

27 (51)

[-8, 31]

Failure

24 (38)

26 (49)

87

101

> 2 years of age

[-10, 15]

Cure

72 (83)

81 (80)

Failure

15 (17)

20 (20)

1 95% CI for (azithromycin – comparator)


Study r 0581 compliance l.jpg
Study R-0581Compliance

Based on patients randomized to their study drug regimen


Study r 0581 treatment related adverse events l.jpg

Amox/Clav N = 173

Azithromycin N = 173

Discontinued due to AE

4 (2%)

7(4%)

Patients w/ AEs

29 (17%)

39 (23%)

Diarrhea

11 (6%)

22 (13%)

Vomiting

7 (4%)

7 (4%)

3 (2%)

9 (5%)

Rash

Study R-0581 Treatment Related Adverse Events*

* Adverse Events greater than 2 percent in either regimen


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Study 1015

Single Dose Therapy


Study 101561 l.jpg
Study 1015

  • Objectives

    • To assess per-pathogen clinical response rates

    • To provide additional data on the safety and toleration of the single dose regimen

  • Design

    • Prospective

    • Open-label

    • Non-comparative

    • Multi-center


Study 1015 visits and assessments l.jpg
Study 1015 Visits and Assessments

*Patients who vomited within 30 minutes were redosed


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Study 1015 Endpoints

Primary Efficacy Endpoint

  • Clinical response by baseline pathogen at day 28

    • Initial local laboratory isolation of pathogen with confirmation by central laboratory

      Secondary Efficacy Endpoints

  • Clinical response at day 28 (test of cure)

  • Clinical response at day 10

    Safety Evaluation


  • Study 1015 patient disposition l.jpg

    Azithromycin

    Evaluation Groups

    Enrolled

    248

    Safety

    248

    Efficacy

    Clinical at Day 28

    242

    Bacteriologic

    127

    Study 1015Patient Disposition


    Study 1015 demographics l.jpg
    Study 1015 Demographics


    Study 1015 results l.jpg
    Study 1015 Results


    Study 1015 clinical outcome l.jpg
    Study 1015 Clinical Outcome

    Azithromycin (%)

    95% CI1 [%]

    Number of Patients

    247

    Day 10

    240

    Success

    213 (89%)

    [85,93]

    Cure

    139

    Improvement

    74

    Failure

    27 (11%)

    Day 28

    242

    Cure

    206 (85%)

    [80,90]

    Failure

    36 (15%)

    1 95% CI for azithromycin


    Study 1015 clinical outcome at day 28 by age l.jpg
    Study 1015 Clinical Outcome at Day 28 by Age

    Azithromycin

    N

    (%)

    95% CI[%]

    < 2 years of age

    83

    Cure

    64

    77

    [67, 87]

    Failure

    19

    23

    > 2 years of age

    159

    Cure

    142

    89

    [84, 94]

    Failure

    17

    11


    Study 1015 clinical outcome per baseline pathogen l.jpg
    Study 1015Clinical Outcome - Per Baseline Pathogen


    Study 1015 mic distribution for s pneumoniae n 67 l.jpg
    Study 1015MIC Distribution for S. pneumoniae (N=67)

    Percent of Patients

    Azithromycin MIC (mg/ml)


    Study 1015 resistant s pneumoniae l.jpg
    Study 1015Resistant S. Pneumoniae

    • S. pneumoniae MIC = 8 g/ml

      • 7 baseline isolates

      • All sensitive to clindamycin

      • All with mef A gene by PCR

    • S. pneumoniae MIC >256 g/ml

      • 5 baseline isolates

      • All resistant to clindamycin

      • All with erm B gene by PCR


    Study 1015 day 28 outcome and mic distribution for s pneumoniae n 66 l.jpg
    Study 1015Day 28 Outcome and MIC Distribution for S. pneumoniae (N=66)

    # of Patients

    Azithromycin MIC (mg/ml)


    Study 1015 patient 0067 failed therapy l.jpg
    Study 1015 Patient 0067 Failed Therapy

    1Susceptible to clindamycin; mef A gene identified

    2Resistant to clindamycin; erm B gene identified


    Study 1015 strains from patient 0067 are clonally distinct l.jpg
    Study 1015Strains From Patient 0067 Are Clonally Distinct

    1 2 3 4

    MIC = 8

    MIC >256


    Study 1015 outcome of s pneumoniae aom by penicillin susceptibility l.jpg

    Penicillin Susceptibility

    Study 1015Outcome of S. pneumoniae AOM by Penicillin Susceptibility

    *Penicillin MIC > 2 mg/ml

    **Penicillin MIC > 0.125 - < 2 mg/ml


    Study 1015 outcome of s pneumoniae aom by penicillin susceptibility76 l.jpg

    Penicillin Susceptibility

    Study 1015Outcome of S. pneumoniae AOM by Penicillin Susceptibility

    *Penicillin MIC > 2 mg/ml

    **Penicillin MIC > 0.125 - < 2 mg/ml


    Study 1015 treatment related adverse events l.jpg
    Study 1015 Treatment Related Adverse Events*

    N

    (%)

    Patients Treated

    248

    Discontinued due to AEs

    1

    (0)

    Patients w/ AEs

    30

    (12)

    Diarrhea

    8

    (3)

    Vomiting

    14

    (6)

    Abdominal Pain

    4

    (2)

    * Adverse Events greater than 1%


    Study 1014 l.jpg

    Study 1014

    Three Day Dosing


    Study 101479 l.jpg
    Study 1014

    • Objectives

      • Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM

    • Design

      • Multicenter, randomized

      • All sites in the United States

      • Double blind, double dummy

        • Azithromycin: 10 mg/kg/day for 3 days

        • Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days

        • Matching placebo for each active study drug


    Study 1014 inclusion criteria symptoms l.jpg
    Study 1014Inclusion Criteria: Symptoms

    1998 FDA Guidance

    1014

    Age

    >6 months

    X

    0.5-11yrs

    Symptoms which help confirm the diagnosis of AOM (%)

    Ear pain (tugging or rubbing)

    X

    921

    Ear fullness

    X

    601

    Either Ear pain or fullness

    97

    Decreased hearing

    X

    251

    Symptoms consistent with AOM (but nonspecific) 2

    Fever

    X

    261

    Irritability

    X

    1 Children had one or more of these signs and symptoms

    2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance)


    Study 1014 inclusion criteria signs of tympanic membrane involvement l.jpg
    Study 1014Inclusion Criteria: Signs of Tympanic Membrane Involvement

    1 Any one of these findings

    2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level


    Study 1014 key exclusion criteria l.jpg
    Study 1014Key Exclusion Criteria

    Other exclusions include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, neutropenia, immunosuppressant therapy, cystic fibrosis, retraction pockets, cholesteatoma, phenylketonuria, anticipated use of probenecid or allopurinol


    Study 1014 visits and assessments l.jpg
    Study 1014 Visits and Assessments

    *Patients who vomited within 30 minutes were redosed


    Study 1014 statistical methods l.jpg
    Study 1014Statistical Methods

    • Primary Endpoint: Clinical Cure

    • Primary Timepoint: Day 28

      • Cure

      • Failure


    Study 1014 statistical methods85 l.jpg
    Study 1014 Statistical Methods

    • Clinical Efficacy Population

      • At least one dose of study medication

      • Diagnosis of AOM at baseline

      • Analyzed at Day 28

        • Return for visit at Day 28

        • Concomitant antibiotic for failure counts as failure


    Study 1014 definition of cure l.jpg
    Study 1014Definition of Cure


    Study 1014 patient disposition l.jpg
    Study 1014Patient Disposition


    Study 1014 demographics l.jpg
    Study 1014Demographics


    Study 1014 results l.jpg
    Study 1014Results


    Study 1014 clinical outcome l.jpg
    Study 1014Clinical Outcome

    Azithromycin (%)

    Amox/Clav (%)

    95% CI1 [%]

    Number of Patients

    188

    185

    Day 10

    185

    181

    Success

    153 (83)

    159 (88)

    [-13,3]

    Cure

    100

    114

    Improvement

    53

    45

    Failure

    32 (17)

    22 (12)

    Day 28

    182

    180

    Cure

    134 (74)

    124 (69)

    [-5, 15]

    Failure

    48 (26)

    56 (31)

    1 95% CI for (azithromycin – comparator)


    Study 1014 clinical outcome at day 28 by age l.jpg
    Study 1014 Clinical Outcome at Day 28 by Age

    Azithromycin

    Amox/Clav

    95% CI1 [%]

    N

    (%)

    N

    (%)

    < 2 years of age

    58

    52

    Cure

    35

    (60)

    30

    (58)

    [-18, 23]

    23

    (40)

    22

    (42)

    Failure

    > 2 years of age

    124

    128

    Cure

    99

    (80)

    94

    (73)

    [-5, 18]

    25

    (20)

    34

    (27)

    Failure

    1 95% CI for (azithromycin – comparator)


    Study 1014 compliance l.jpg
    Study 1014Compliance

    Based on patients randomized to their study drug regimen


    Study 1014 treatment related adverse events l.jpg
    Study 1014 Treatment Related Adverse Events*

    Azithromycin

    Amox/Clav

    N

    %

    N

    %

    188

    185

    Patients Treated

    1

    (1)

    2

    (1)

    Discontinued due to AE

    20

    (11)

    37

    (20)

    Patients with AE

    11

    27

    (6)

    (15)

    Diarrhea

    (2)

    4

    2

    (1)

    Vomiting

    0

    (0)

    (4)

    8

    Rash

    * Adverse events greater than 2% in either treatment regimen



    Acute otitis media summary clinical cure at day 28 l.jpg
    Acute Otitis MediaSummary Clinical Cure at Day 28

    Study

    Azithromycin 3 Day

    Azithromycin Single Dose

    Comparator

    95% CI

    [-7, 15]

    R-0581Az-Amox/Clav

    112/151 (74%)

    108/154 (70%)

    1015

    206/242 (85%)

    [-5, 15]

    1014

    Az-Amox/Clav

    134/182 (74%)

    124/180 (69%)

    [-5, 25]

    [-15, 17]

    95-001AzSD-CTX Az3D-CTX

    51/66 (77%)

    56/65 (86%)

    49/64 (77%)


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    Effect of Age on Clinical Outcome< 2 years of age

    *Clinical success; **Clinical cure; 1Single dose regimen


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    Summary of Clinical TrialsClinical Cure by Baseline Pathogen at Day 28


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    Treatment Related Adverse Events Azithromycin Regimens for AOM Vs. Comparator*

    Azithromycin Duration (Days)

    Comparator

    1

    3

    5

    Number of Patients

    487

    254

    888

    1105

    Patients with Related Adverse Events

    66 (14%)

    26 (10%)

    69 (8%)

    254 (23%)

    Patients with common AE’s:

    Diarrhea

    21 (4%)

    14 (6%)

    31 (3%)

    171 (16%)

    Vomiting

    24 (5%)

    4 (2%)

    11 (1%)

    41 (4%)

    Abdominal pain

    7 (1%)

    1 (<1%)

    13 (1%)

    23 (2%)

    Nausea

    6 (1%)

    0 (0%)

    5 (1%)

    18 (2%)

    Rash

    4 (1%)

    0 (0%)

    6 (1%)

    27 (2%)

    *Pivotal studies from 1, 3 and 5 day programs; All AE’s > 2 %


    Treatment related adverse events azithromycin regimens for aom vs comparator99 l.jpg
    Treatment Related Adverse EventsAzithromycin Regimens for AOM Vs. Comparator*

    Azithromycin Duration (Days)

    Comparator

    1

    3

    5

    Number of Patients

    487

    254

    888

    1105

    Patients with Related Adverse Events

    66 (14%)

    26 (10%)

    69 (8%)

    254 (23%)

    Related Adverse Events/Patient Year

    6.7

    7.4

    9.8

    22.7

    *Pivotal studies from 1, 3 and 5 day programs


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    Azithromycin for Acute Otitis Media

    • Chemistry/Pharmacokinetics

    • Microbiology

    • Clinical Program

      • Overview of Five Day Program

      • Single Dose

      • Three Day Dosing

      • Focus on Selected Topics

    • Conclusion


    Focus on selected topics l.jpg
    Focus on Selected Topics

    • Vomiting of the single dose therapy

    • Historical comparison of cure rates at day 28

    • Timing of the clinical assessment



    Patients who vomited single dose therapy l.jpg

    Total

    52/487 (10.7%)

    On the first day

    36/487 (7.4%)

    Patients Who Vomited Single Dose Therapy

    Clinical Outcome for Children Who Vomited on Day 1

    Day 14

    Day 28

    Vomited

    No Vomiting

    Vomited

    No Vomiting

    Cure/Improved

    31 (91%)

    383 (89%)

    29 (85%)

    345 (81%)

    Fail

    3 (9%)

    47 (11%)

    5 (15%)

    79 (19%)

    Missing

    2

    2


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    Individual values for subjects who vomited >2 hours post-dose

    AUC (mg·hr/ml)

    2 g

    (n=36)

    2 g

    (n=36)

    2 g

    (n=35)

    2 g

    (n=35)

    3 g

    (n=8)

    3 g

    (n=8)

    3 g

    (n=27)

    3 g

    (n=27)

    * AUC(0-24); ** AUC(0-infinity); ***AUC(0-288)

    AzithromycinAUC Values Following 2g and 3g Single Doses


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    Historical Comparison of Cure Rates at Test of Cure Visit (Day 28)

    Clinical response vs beta-lactams

    • Empiric treatment

    • S. pneumoniae at baseline

    • H. influenzae at baseline


    Azithromycin vs beta lactams comparative trials for aom clinical cure at day 28 l.jpg

    Azithromycin 5 Day (Day 28)

    Pfizer, 178 (Amox/Clav)

    Pfizer, 134 (Amox/Clav)

    Pfizer, 128 (Amox/Clav)

    Dagan, 2000 (Amox/Clav)

    Azithromycin 3 Day

    Rodriquez, 1996 (Cefaclor)

    Pestalozza, 1992 (Amox/Clav)

    Pfizer, 1014 (Amox/Clav)

    Pfizer, 95-001 (Ceftriaxone)

    Azithromycin 1 Day

    Pfizer, R-0581 (Amox/Clav)

    Pfizer, 95-001 (Ceftriaxone)

    Overall

    Azithromycin vs Amox/Clav (N=1864)

    All Studies ( N=2127)

    Azithromycin Vs Beta-lactamsComparative Trials for AOM: Clinical Cure at Day 28

    % Difference (95% CI)

    Favors Comparator

    Favors Azithromycin


    S pneumoniae clinical outcome test of cure visit day 17 35 l.jpg

    Clinical Success (Day 28)

    Azithromycin – 5 Day

    Cefpodoxime proxetil

    Amox/Clav (Augmentin ES)

    Clinical Cure

    Cefprozil

    Cefdinir 5 Day

    Cefdinir 10 Day

    Azithromycin – 1 Day*

    Ceftriaxone

    Azithromycin – 3 Day*

    S. pneumoniae Clinical Outcome Test of Cure Visit (Day 17-35)*

    *Product labels (PDR, 2001);

    Summary basis of approval;

    Sponsor study report

    % Successful Clinical Outcome, (95% CI)


    H influenzae clinical outcome test of cure visit day 17 35 l.jpg

    Clinical Success (Day 28)

    Azithromycin 5 Day

    Cefpodoxime proxetil

    Amox/Clav (Augmentin ES)

    Cefixime

    Clinical Cure

    Cefprozil

    Cefdinir 5 Day

    Azithromycin Single Dose

    Ceftriaxone

    Azithromycin 3 Day

    *Product labels (PDR, 2001);

    Summary basis of approval;

    Sponsor study report

    % Successful Clinical Outcome (95% CI)

    H. influenzae Clinical OutcomeTest of Cure Visit (Day 17-35)*

    Cefdinir 10 Day


    Timing of clinical assessment l.jpg

    Timing of Clinical Assessment (Day 28)

    Early (on therapy) time points

    Additional antibiotic

    Analgesics use

    Parental questionnaire

    Day 10-14

    Overall clinical response vs beta-lactams

    Clinical outcome with H. influenzae at baseline


    Time to additional antibiotic use l.jpg
    Time to Additional Antibiotic Use (Day 28)

    Proportion without

    Additional Antibiotic

    Day of First Antibiotic Use

    • Azithromycin studies R-0581, 95-001, 1014

    • Comparators combine amoxicillin/clavulanate and ceftriaxone

    • Time to failure = time to concomitant antibiotic use for failure


    Percent patients on analgesics antipyretics by study day r 0581 l.jpg
    Percent Patients on Analgesics/Antipyretics (Day 28)By Study Day – R-0581

    Percentage

    Days


    Percent patients on analgesics antipyretics by study day 1014 l.jpg
    Percent Patients on Analgesics/Antipyretics (Day 28)By Study Day – 1014

    Percentage

    Days


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    Study R-0581 (Day 28)Parental Questionnaire

    How Sick Overall Has Child Been?

    Not at all

    Moderately

    Extremely


    Timing of clinical assessment114 l.jpg

    Timing of Clinical Assessment (Day 28)

    Early time points

    Day 10-14

    Overall clinical response vs beta-lactams

    Clinical outcome with H. influenzae at baseline


    Azithromycin vs beta lactams comparative trials for aom clinical success at day 14 l.jpg

    Azithromycin 5 Day (Day 28)

    Pfizer, 178 (Amox/Clav)

    Pfizer, 134 (Amox/Clav)

    Pfizer, 128 (Amox/Clav)

    Dagan, 2000 (Amox/Clav)

    Azithromycin 3 Day

    Rodriguez, 1996 (Cefaclor)

    Dagan, 2000 (Cefaclor)

    Mohs, 1993 (Amoxicillin)

    Arguedas, 1996 (Amox/Clav)

    Pestalozza, 1992 (Amox/Clav)

    Daniel, 1993 (Amox/Clav)

    Principi, 1995 (Amox/Clav)

    Schaad 1993 (Amox/Clav)

    Pfizer, 1014 (Amox/Clav)

    Pfizer, 95-001 (Ceftriaxone)

    Azithromycin 1 Day

    Pfizer, R-0581 (Amox/Clav)

    Pfizer, 95-001 (Ceftriaxone)

    Overall

    Azithromycin vs Amox/Clav (N=3271)

    All Studies (N=3956)

    Azithromycin Vs Beta-lactamsComparative Trials for AOM: Clinical Success at Day 14

    % Difference (95% CI)

    Favors Comparator

    Favors Azithromycin


    Timing of clinical assessment116 l.jpg

    Timing of Clinical Assessment (Day 28)

    Early time points

    Day 10-14

    Overall clinical response vs beta-lactams

    Clinical outcome with H. influenzae at baseline


    H influenzae clinical outcome end of therapy day 7 15 l.jpg

    Clinical Success (Day 28)

    Azithromycin 1 Day Overall

    Azithromycin 3 Day

    Azithromycin 5 Day

    Cefpodoxime proxetil

    Amox/Clav (Per Protocol)

    Amox/Clav (ITT)

    Cefixime

    Cefaclor

    Ceftibuten

    Cefuroxime axetil

    Clarithromycin

    Erythromycin

    Erythromycin + sulfa

    Clinical Cure

    Ceftriaxone (Per Protocol)

    Loracarbef

    % Clinical Success (95% CI)

    H. influenzae Clinical OutcomeEnd of Therapy (Day 7-15)*

    *Product labels (PDR, 2001);

    Summary basis of approval;

    Sponsor study report


    Azithromycin for acute otitis media118 l.jpg
    Azithromycin for Acute Otitis Media (Day 28)

    • Chemistry/Pharmacokinetics

    • Microbiology

    • Clinical Data

    • Conclusion


    Conclusions azithromycin for acute otitis media l.jpg
    Conclusions (Day 28)Azithromycin for Acute Otitis Media

    • Effective, empiric treatment of acute otitis media

      • As a single dose or over three days

    • Well tolerated, safe antibiotic

    • Optimizes compliance

      • Complete course of therapy in single dose

      • Eases burden on the caregiver