PFIZER INC. Study Centres: A total of 8 centres in France took part in the study.

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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-F PROTOCOL TITLE: A Study of the Efficacy and Tolerance of Low-Dose Oral Doxycycline Monohydrate, Taken for a Period of Two and a Half Months, in Patients With Refractory Acne Vulgaris Study Centres: A total of 8 centres in France took part in the study. Study Initiation Date and Primary Completion or Completion Dates: Information not available. Phase of Development: Information not available. Study Objectives: To confirm the efficacy and tolerance of a new formulation of doxycycline monohydrate (divisible tablets of 100 mg) in relation to the effects on inflammatory lesions in subjects presenting with refractory acne vulgaris. METHODS Study Design: This was an open-label, multicentre study performed in 8 dermatology clinics. Subjects presenting with refractory acne vulgaris were enrolled into this study to confirm the efficacy and tolerance of a new formulation of doxycycline monohydrate (divisible tablets of 100 mg) in relation to the effects on inflammatory lesions. The duration of subject participation in this study was 75 days (subjects received 100 mg daily for the first 14 days and subsequently 50 mg daily for the following 2 months). Eligible subjects were enrolled in the study during screening visit. Subjects were assessed for efficacy at the follow-up visits at Day 14 and. Number of Subjects (Planned and Analysed): The planned sample size for the study was 100 subjects. A total of 106 subjects were enrolled and treated, with 97 subjects being available for analyses at the Day 14 visit. Diagnosis and Main Criteria for Inclusion: Subjects presented with acne vulgaris of more than 1 year duration with eruptive inflammatory cutaneous lesions with or without associated non-inflammatory lesions were enrolled in the study. Page 1

2 Study Treatment: Subjects were treated with doxycycline monohydrate, in the form of divisible tablets, for up to 75 days. Subjects received 100 mg daily for the first 14 days and subsequently 50 mg daily for the following 2 months. Efficacy Evaluations: Efficacy was evaluated using the following outcome measures: Overall clinical result/outcome assessed at both at Day 14 and ; A reduction in the severity of the disease and the number of lesions (comedones, whiteheads, papules, pustules and small abscesses) assessed at Day 14 and ; The clinical score, ranging from 0 60, calculated at Day 0, Day 14 and, and defined as: E x (S + C + P + I + A + E); where E = extent of lesions (graded 1 4); S = appreciation of seborrhoea (graded 0 3); C = number of comedones (graded 0 3); P = number of papules and pustules (graded 0 3); I = number of inflammatory lesions (graded 0 3); A = number of cutaneous abscesses (graded 0 3) Clinical result in terms of effects on inflammatory lesions assessed at both at Day 14 and ; Reduction in the number of inflammatory cutaneous lesions on the right hand side of the face assessed at Day 0, Day 14 and. Safety Evaluations: Safety was evaluated by monitoring adverse events (AEs) and serious AEs (SAEs) throughout the duration of the study. Statistical Methods: Information not available. RESULTS Subject Disposition and Demography: A total of 40 male and 66 female subjects aged between 15 and 44 years (mean age 23 years) were included in this study. All subjects presented with acne vulgaris of more than 1 year s duration with eruptive inflammatory cutaneous lesions with or without associated non-inflammatory lesions. The severity of the disease was assessed at study entry as severe in 24 subjects (22.9%), moderate in 75 subjects (71.4%) and mild in 6 subjects (5.7%). Page 2

3 Efficacy Results: Overall Clinical Result/Outcome Globally, the clinical outcome was assessed as satisfactory in more than 95% of cases at both Day 14 and, as shown below in Table 1. Table 1. Overall Clinical Result Overall Clinical Result Day 14 Good 53 (54.6) 40 (48.2) Moderate 43 (44.3) a 40 (48.2) Poor 1 (1.0) b 3 (3.6) All 97 (100.00) 83 (100) a Two subjects were withdrawn due to lack of efficacy; b One subject was withdrawn due to lack of efficacy. Type of Lesions A reduction in the severity of the disease and the number of lesions (comedones, whiteheads, papules, pustules and small abscesses) was also observed at Day 14, which was sustained at. Table 2 below shows the types of lesions and the number of subjects affected at Day 0, Day 14 and. Table 2. Type of Lesions Type of Lesions Day 0 Day 14 Comedones 93 (88.6) 81 (83.5) 59 (71.1) Whiteheads 72 (68.6) 58 (59.8) 34 (41.0) Papules 102 (97.1) 85 (87.6) 54 (65.1) Pustules 96 (91.4) 42 (43.3) 25 (30.1) Small abscesses 42 (40.0) 4 (4.1) 4 (4.8) Clinical Score The clinical score, calculated at Day 0, Day 14 and showed a statistically significant reduction during the course of the study (paired t-test, p=0.0001). Table 3 below shows the clinical scores calculated over the course of the study. Table 3. Clinical Score Clinical Score Mean Standard Deviation Minimum Maximum Number of Subjects Day Day Day 0-Day 14 a Day 14- b Day 0- c a Paired t-test: p=0.0001; b Paired t-test: p=0.077; c Paired t-test: p= Page 3

4 Clinical Result on Inflammatory Lesions The results, in terms of effects in inflammatory lesions, were assessed as good in 62% of cases at Day 14 and 52% of cases at. Similarly, these results were assessed as moderate in 37% of cases at Day 14 and 46% of cases at (Table 4). Table 4. Clinical Result on Inflammatory Lesions Clinical Result on Inflammatory Lesions Day 14 Good 60 (61.9) 43 (52.4) Moderate a 36 (37.1) 38 (46.3) Poor b 1 (1.0) 1 (1.2) All 97 (100.00) 82 (100) a Two subjects were withdrawn due to lack of efficacy; b One subject was withdrawn due to lack of efficacy. The mean number of inflammatory cutaneous lesions counted on the right side of the face was 9.9, 3.5 and 2.9 at Day 0, Day 14 and, respectively, with a net reduction in the size of lesions. Study treatment also prevented new acneic eruptions in 79.5% of cases during the course of the study. Safety Results: Twelve subjects (11.4%) reported 1 AEs during the course of the study. All were assessed as non-serious and most of them were of a gastrointestinal nature, which is well recognised with treatments of this type. Adverse events reported by the subjects are presented in Table 5 below. The reported adverse events were as follows: gastric pain (3 subjects), nausea (2 subjects), diarrhoea (2 subjects), abdominal pain with nausea (1 subject), genital candidiasis (1 subject), mild fatigue (1 subject), joint and muscle pain (1 subject) and axilliary hydroadenitis (1 subject). No particular measures were necessary in any of these cases. Two subjects prematurely discontinued study treatment as a consequence of AEs, 1 subject for axilliary hydroadenitis and 1 for gastric pain. Page 4

5 Table 5. Adverse Events Data Reported by Subject Adverse Event Total Daily Dose at AE Onset (mg) Start of Drug to AE Onset (Days) Severity (Mild, Moderate, Severe) Gastralgia Mild Fatigue Mild Axillary hydroadenitis a Moderate Joints and muscle pain Moderate Diarrohea Mild Nausea Mild Abdominal pain Moderate Gastralgia a Moderate Genital candidiasis Moderate Stomach pains and Moderate nausea Nausea Severe Diarrohea Mild a Treatment was permanently discontinued due to the adverse event. Whether the adverse event was due to study treatment was unknown in all cases; adverse events were cleared in all subjects by the end of study treatment. AE: Adverse event. CONCLUSIONS: This study confirms the global efficacy, and in particular, the efficacy in terms of effects on inflammatory lesions, of doxycycline monohydrate when prescribed at the dose of 100 mg daily for 14 days and subsequently 50 mg daily for the following 2 months. The results also confirm the good tolerability of this treatment. Page 5