EMA Paediatric Web SynopsisProtocol DXC-P-86-002 – 05 December 2011 – Final

Page 1

PFIZER INC.

These results are supplied for informational purposes only.Prescribing decisions should be made based on the approved package insert.

For publications based on this study, see associated bibliography.

PROPRIETARY DRUG NAME®/GENERIC DRUG NAME: Vibramicina®/Doxycycline

PROTOCOL NO.: DXC-P-86-002

PROTOCOL TITLE: Treatment of Acute Respiratory Tract Infections with a New Formulation of Doxycycline

Study Centres: The study was conducted at 46 centres in Portugal.

Study Initiation Date and Completion Date: 1986 to 1988 (full information not available).

Phase of Development: Information not available.

Study Objectives: To demonstrate the rapid onset of action, potency and efficacy of doxycycline using 100 mg dispersible tablets in the treatment of acute respiratory tract infections.

METHODS

Study Design: This was an open-label, non-comparative multicentre study, conducted to evaluate the efficacy and safety of doxycycline using 100 mg dispersible tablets in subjects with acute respiratory tract infections. Subjects received a regular dosage regimen of doxycycline; however, investigators were permitted to use other alternative dosages ranging from one 100 mg doxycycline dispersible tablet daily to two 100 mg tablets twice daily(BID) for up to 10 days, or more as needed. This made it possible to evaluate how doxycycline is generally used by physicians.

Number of Subjects (Planned and Analysed): Information for the number of subjects planned to be enrolled in the study is not available; although a total of 775 subjects were treated and analysed in the study.

Diagnosis and Main Criteria for Inclusion: Subjects were male or female, aged 8 years or older; presenting with acute respiratory tract infection with clinical symptoms of fever, cough, pain, expectoration (as quantity, type, viscosity) and inflammatory symptoms; and clinical conditions such as acute exacerbation of chronic bronchitis, acute bronchitis, tonsillitis, sinusitis, pharyngitis, otitis, pneumonia, tracheitis and bronchopneumonia.

Study Treatment: The subjects were instructed to take from 100 mg doxycycline once daily to 200 mg doxycycline BID in the form of dispersible tablets for up to 10 days, or more if

0901

77e1

8299

655b

\App

rove

d\A

ppro

ved

On:

08-

Dec

-201

1 06

:54

EMA Paediatric Web SynopsisProtocol DXC-P-86-002 – 05 December 2011 – Final

Page 2

needed. Investigators were reminded of the need for a regular dosage regimen for doxycycline, but were allowed to use other alternative dosages, as needed.

Efficacy Evaluations: Subjects were evaluated for the presence and severity of the following parameters:

fever – recorded as 37-37.5oC, 37.6-38.5oC, 38.6-39.5oC or 39.6-40.0oC

cough – rated as none, moderate or severe

pain – rated as none, moderate or severe

expectoration – rated by:

o quantity (none, scant or abundant)

o type (purulent, mucopurulent or mucous)

o viscosity (none, reduced, moderate or severe)

inflammatory symptoms – rated as none, moderate or severe

clinical conditions – rated as poor, fair, good or very good.

The clinical conditions to be monitored were acute exacerbation of chronic bronchitis, acute bronchitis, tonsillitis, sinusitis, pharyngitis, otitis, pneumonia, tracheitis, bronchopneumonia, etc.

Subjects were evaluated prior to treatment for the presence and severity of fever, cough, pain, expectoration (quantity, type and viscosity), and inflammatory symptoms. The final evaluation was performed after the protocol case report forms had been completely filled out; taking into account clinical efficacy, the presence or absence of side effects, and how quickly the treatment worked.

Safety Evaluations: At each visit, all side effects, and their severity and imputability were recorded.

Statistical Methods: Information not available

RESULTS

Subject Disposition and Demography: A total of 775 subjects were treated with the studydrug. Of these subjects, 380 were males and 380 were females; gender was not indicated for 11 subjects and age was not indicated for 3 subjects. Subject distribution by age group, gender and clinical diagnosis is shown in Table 1 and Table 2.

0901

77e1

8299

655b

\App

rove

d\A

ppro

ved

On:

08-

Dec

-201

1 06

:54

EMA Paediatric Web SynopsisProtocol DXC-P-86-002 – 05 December 2011 – Final

Page 3

Table 1. Subject Distribution by Age, Gender and Clinical Diagnosis

SexTotal Number of Subjects Male Female

Age Group (years), n8-12 26 12 1413-20 76 41 3521-30 134 63 7131-40 153 73 8041-50 116 68 4851-60 116 54 62≥60 140 69 71

Total 761 380 380

Clinical Diagnosis, n (%)Acute exacerbation of chronic bronchitis

153 (19.74) 98 (64.4) 54 (35.5)

Acute bronchitis 108 (13.93) 50 (47.6) 55 (52.3)Tonsillitis 139 (17.93) 54 (39.7) 82 (60.2)Sinusitis 103 (13.29) 56 (54.3) 47 (45.6)Pharyngitis 91 (11.74) 40 (43.9) 51 (56.0)Otitis 46 (5.93) 24 (53.3) 21 (46.6)Bronchopneumonia 44 (5.67) 16 (36.3) 28 (63.3)Pneumonia 44 (5.67) 19 (45.2) 23 (54.7)Tracheitis 18 (2.32) 11 (61.1) 7 (38.8)Other 29 (3.74) 13 (46.4) 15 (53.5)

Total 775 (99.96) 381 (49.86) 383 (50.13)n=Number of subjects

Table 2. Subject Distribution by Age Group, Gender and Clinical Diagnosis

Age Group (Years)Gender

8-12 13-20 21-30 31-40 41-50 51-60 ≥60 TotalClinical Diagnosis, n M F M F M F M F M F M F M F N %Acute exacerbation of chronic bronchitis

- - 1 1 3 2 5 5 13 4 28 17 48 25 152 19.97

Acute bronchitis 1 1 3 1 10 5 11 13 13 10 6 10 6 15 105 13.79Tonsillitis 8 3 17 20 9 24 13 17 7 7 - 5 - 6 136 17.87Sinusitis 1 1 6 3 16 12 18 11 8 6 4 10 3 3 102 13.40Pharyngitis - 1 5 5 11 11 7 18 9 6 5 7 2 3 90 11.82Otitis 1 6 4 3 5 5 8 4 4 1 2 2 - - 45 5.91Broncho-pneumonia

- - 1 - 2 2 2 6 5 5 1 5 5 10 44 5.78

Pneumonia - 1 2 1 3 5 1 4 2 3 7 2 4 7 42 5.51Tracheitis 1 - 1 1 2 2 4 1 3 1 - 2 - - 18 2.36Other - 1 1 - 2 3 4 1 4 5 1 2 1 2 27 3.54

12 14 41 35 63 71 73 80 68 48 54 62 69 71 761Total, N (%)

26 (3.41) 76 (9.98)134

(17.60)153

(20.10)116

(15.24)116

(15.24)140

(18.39)Note: Age was not indicated for 3 subjects; sex was not indicated for 11 subjects.F=Female; M= Male; N=Total number of subjects. n=Number of subjects

Efficacy Results: Over the course of treatment, a predominance of the 200 mg BID dose of doxycycline was confirmed (Table 3).

0901

77e1

8299

655b

\App

rove

d\A

ppro

ved

On:

08-

Dec

-201

1 06

:54

EMA Paediatric Web SynopsisProtocol DXC-P-86-002 – 05 December 2011 – Final

Page 4

Table 3. Progression in Dosages

Number (%) of SubjectsDosage Treatment

Day 1Treatment

Day 3Treatment

Day 5Treatment

Day 7Treatment

Day 10100 mg (once daily) 25 (3.2) 253 (33.1) 343 (46.2) 304 (47.1) 157 (37.6)200 mg (once daily) 316 (41.4) 101 (13.2) 73 (9.8) 68 (10.5) 52 (12.4)200 mg (twice daily) 422 (55.3) 409 (53.6) 326 (43.9) 273 (42.3) 208 (49.8)Other - - - - -Total 763 763 742 645 417

Efficacy evaluation of inflammatory symptoms is summarised in Table 4. A total of 92.8% of cases with very good or good efficacy were obtained in this study.

Table 4. Evaluation of Efficacy

Number (%) of SubjectsClinical Diagnosis Very Good Good Fair Nil Not ReportedAcute exacerbation of chronic bronchitis, n=153

68 (44.4) 64 (41.8) 19 (12.4) 2 (1.3) -

Acute bronchitis, n=108

65 (60.1) 36 (33.3) 5 (4.6) 1 (0.9) 1 (0.9)

Tonsillitis, n=139 100 (71.9) 35 (25.1) 4 (2.8) - -Sinusitis, n=103 66 (64.0) 30 (29.1) 6 (5.8) - 1 (0.9)Pharyngitis, n=91 63 (69.2) 25 (27.4) 3 (3.2) - -Otitis, n=46 34 (73.9) 8 (17.3) 3 (6.5) 1 (2.1) -Bronchopneumonia, n=44

30 (68.1) 14 (31.8) - - -

Pneumonia, n=44 31 (70.4) 11 (25.0) 2 (4.5) - -Tracheitis, n=18 14 (77.7) 3 (16.6) - - 1 (5.5)Other, n=29 17 (58.6) 6 (20.6) 5 (17.2) 1 (3.4) -Total, N=775 488 (62.9) 232 (29.9) 47 5 3

92.8% 6.06% 0.64% 0.38%N=Total number of subjects; n=Number of subjects

Qualitative course of expectoration and the course of cough are presented in Table 5 and Table 6 respectively, which shows significant improvement. Cough improved as a function of clinical improvement.

0901

77e1

8299

655b

\App

rove

d\A

ppro

ved

On:

08-

Dec

-201

1 06

:54

EMA Paediatric Web SynopsisProtocol DXC-P-86-002 – 05 December 2011 – Final

Page 5

Table 5. Qualitative Course of Expectoration

Number (%) of Subjects

ExpectorationTreatment

Day 0Treatment

Day 2Treatment

Day 5Treatment

Day 10Treatment

Day 15Purulent 181 (42.5) 136 (36.2) 18 (6.1) 0 (0) -Mucopurulent 191 (44.9) 190 (50.6) 135 (45.9) 21 (17.3) -Mucous 53 (12.4) 49 (13.0) 141 (47.9) 100 (82.6) -Total 425 375 294 121 -Cumulative % of subjects with no expectoration

- 11.76 30.82 71.52 -

Table 6. Qualitative Course of Cough

Number (%) of Subjects

Cough (Severity)Treatment

Day 0Treatment

Day 2Treatment

Day 5Treatment

Day 10Treatment

Day 15Severe 262 206 22 2 -Moderate 190 178 248 96 -None 151 128 250 271 -Total 603 512 520 369 -

Safety Results: Evaluation of tolerance is presented in Table 7. A total of 574 subjects (91.46%) showed very good or good tolerance.

Table 7. Evaluation of Tolerance

Number (%) of Subjects

Clinical DiagnosisVery Good Good Fair Poor Not

ReportedAcute exacerbation of chronic bronchitis, n=153

111 (72.5) 25 (16.3) 13 (8.4) 4 (2.6) –

Acute bronchitis, n=108 75 (69.4) 21 (19.4) 8 (7.4) 3 (2.7) 1 (0.9)Tonsillitis, n=139 104 (74.8) 26 (18.7) 9 (6.4) - -Sinusitis, n=103 75 (72.8) 18 (17.4) 7 (6.7) 2 (1.9) 1 (0.9)Pharyngitis, n=91 69 (75.8) 14 (15.3) 6 (6.5) 2 (2.1) -Otitis, n=46 35 (76.0) 8 (17.3) 2 (4.3) 1 (2.1) –Bronchopneumonia, n=44 32 (72.7) 8 (18.1) 2 (4.5) 2 (4.5) –Pneumonia, n=44 37 (84.0) 6 (13.6) – 1 (2.2) –Tracheitis, n=18 15 (83.3) 2 (11.1) - - 1 (5.5)Other, n=29 21 (72.4) 7 (24.1) – 1 (3.4) –Total, N=775 574 (91.46) 135 (-) 47 (6.06) 16 (2.06) 3 (0.38)n=Number of subjects

CONCLUSIONS: Comparing this study with others conducted previously, its confirmed that the results obtained were comparable.

With respect to tolerance, this formulation is preferred by the youngest and oldest age groups. In the first instance, it may be because the dispersible form was much easier to take, and in the second instance, it may be because this was a subject group with chronic pathology that is dependent on a lot of medication; hence the greater acceptance of this formulation had been obtained.

0901

77e1

8299

655b

\App

rove

d\A

ppro

ved

On:

08-

Dec

-201

1 06

:54

EMA Paediatric Web SynopsisProtocol DXC-P-86-002 – 05 December 2011 – Final

Page 6

Regardless, for this form of doxycycline, a total of 91.5% of cases with very good and good tolerance was remarkable.

It should also be underscored that doxycycline had resisted, in a very positive manner, the natural detrimental effects of time and competition with other antibiotics also targeted at diseases of the same body system.

Additionally, it should be emphasised that the 92.8% very good and good results obtained in this trial with the dosage indicated by the laboratory and traditionally accepted for doxycycline leads to the belief that the incidence of antibiotic resistance is still markedly low.

0901

77e1

8299

655b

\App

rove

d\A

ppro

ved

On:

08-

Dec

-201

1 06

:54