Clinical Trial Study Synopsis

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1 Clinical Trial Study Synopsis This file is posted on the Bayer HealthCare Clinical Trials Registry and Results website and is provided for patients and healthcare professionals to increase the transparency of Bayer's clinical research. This document is not intended to replace the advice of a healthcare professional and should not be considered as a recommendation. Patients should always seek medical advice before making any decisions on their treatment. Healthcare Professionals should always refer to the specific labeling information approved for the patient's country or region. Data on this website should not be considered as prescribing advice. The study listed may include approved and non-approved formulations or treatment regimens. Data may differ from published or presented data and are a reflection of the limited information provided here. The results from a single trial need to be considered in the context of the totality of the available clinical research results for a drug. The results from a single study may not reflect the overall results for a drug. The following information is the property of Bayer HealthCare AG. Reproduction of all or part of this report is strictly prohibited without prior written permission from Bayer HealthCare AG. Commercial use of the information is only possible with the written permission of the proprietor and is subject to a license fee. Please note that the General Conditions of Use and the Privacy Statement of bayerhealthcare.com apply to the contents of this file.

2 2. Study synopsis Title of the study: Investigators : Study centers Publications (references): Double-blind, randomized, placebo-controlled, single dose, parallel group study evaluating efficacy and safety of 1000 mg acetylsalicylic acid and 1000 mg paracetamol in adult patients with sore throat associated with a common cold IMPACT R Eccles, Coordinating investigator 1) M Jawad, 2) M Salman 3) S Taylor 4) J Robinson 5) I Lodhi, N Kola 6) G Dovey 7) H Shaw 8) J Fraser 1) Cardiff, United Kingdom 2) Birmingham, United Kingdom 3) Chorley, United Kingdom 4) Crosby, United Kingdom 5) Liverpool, United Kingdom 6) Manchester, United Kingdom 7) Reading, United Kingdom 8) Wrightington, United Kingdom None Period of study: 04 Nov 2003 to 09 Mar 2005 Clinical phase: IV

3 Objectives: Primary study objective was to evaluate pain intensity differences to baseline (PID) of ASA for a 6 hour period after administration of study medication (SPID 0-6 ) in comparison to paracetamol. Secondary study objectives were: - to evaluate SPID 0-6 of ASA in comparison to placebo; - to evaluate total pain relief (TOTPAR) for the 6 hours after administration of study medication TOTPAR 0-6 of ASA in comparison to paracetamol; - to evaluate total pain relief for the 6 hours after administration of study medication TOTPAR 0-6 of ASA in comparison to placebo; - to evaluate pain relief of ASA, paracetamol and placebo for each assessment; - to evaluate PID of ASA, paracetamol and placebo for each assessment in comparison to baseline; - to evaluate SPID 0-2, and SPID 0-4 for ASA in comparison to placebo; - to evaluate TOTPAR 0-2, and TOTPAR 0-4 for ASA in comparison to placebo; - to evaluate other symptoms of URTI (headache, sinus pressure/pain, feverish discomfort, muscle aches and pains) 2 hours after administration of study medication; - to evaluate symptoms of common cold in the 24-hour period before administration of study medication; - to assess drug safety. Methodology (design of study): This was a double-blind, randomized, placebo and active controlled, 3 parallel treatment groups (1000 mg acetylsalicylic acid (ASA), 1000 mg paracetamol, and placebo), single dose, multicenter, national study with a three-stage group sequential adaptive test plan with planned sample size adjustments at the two interim analyses.

4 Number of patients: Diagnosis and main criteria for inclusion: Test product, dose and mode of administration, batch number: Duration of treatment: 509 patients enrolled, thereof: 508 patients treated according to Intention-to-treat (ITT) and 489 patients per-protocol (PP), Treatment A (1000 mg ASA): 206 patients (ITT), 202 patients (PP) Treatment B (1000 mg paracetamol): 202 patients (ITT), 190 patients (PP) Treatment C (placebo): 100 patients (ITT), 97 patients (PP) 1 withdrawal 286 females and 222 males (ITT) (279 females and 210 males (PP)) Male and female patients at least 18 years of age with sore throat associated with a common cold fulfilling the following inclusion criteria: - Onset of common cold (URTI) in the past 5 days ( h). - History of at least 4 symptoms associated with URTI in the past 24 hours out of runny nose, stuffy nose, sneezing, wet cough, dry cough, sweating, earache, ear fullness, sinus pressure/pain, head heaviness, muscle aches and pains, feverish discomfort, chills, hoarseness, sore throat, scratchy throat, and headache. - Current sore throat confirmed by a score 6 on the pain intensity scale. - Findings that confirmed the presence of tonsillo-pharyngitis. - Agreement to comply with the study requirements. - Informed consent obtained in writing prior to enrolment in the study. ASA, 2 tablets each containing 500 mg, batch no.: BX01B68 placebo to paracetamol, 2 tablets, batch no.: BX01AZT oral administration with 240 ml of water Inpatient assessment period of 2 hours and a home assessment period of 4 hours.

5 Reference therapy, dose and mode of administration, batch number: paracetamol, 2 tablets each containing 500 mg, batch no.: BX01BW6, W4AA3114 placebo to ASA, 2 tablets, batch no.: BX018TP oral administration with 240 ml of water placebo to ASA, 2 tablets, batch no.: BX018TP placebo to paracetamol, 2 tablets, batch no.: BX01AZT oral administration with 240 ml of water Criteria of evaluation: Primary efficacy criterion: - Sore throat pain (11-category vertical ordinal scale). - SPID 0-6 at 30, 60, 90, 120, 150, 180, 210, 240, 270, 300, 330, and 360 minutes after administration of study medication. Secondary efficacy criteria: - Pain relief (7-category ordinal verbal rating scale). - TOTPAR 0-6 at 30, 60, 90, 120, 150, 180, 210, 240, 270, 300, 330, and 360 minutes after administration of study medication. - Pain relief at each assessment. - PID at each assessment in comparison to baseline. - SPID 0-4 at 30, 60, 90, 120, 150, 180, 210, and 240 minutes after administration of study medication. - SPID 0-2 at 30, 60, 90, and 120 minutes after administration of study medication. - TOTPAR 0-4 at 30, 60, 90, 120, 150, 180, 210, and 240 minutes after administration of study medication. - TOTPAR 0-2 at 30, 60, 90, and 120 minutes after administration of study medication. - Other symptoms of URTI (sore throat, sinus pressure/pain, feverish discomfort, muscle aches and pains) were to be assessed 120 minutes after administration of study medication (11-category vertical ordinal scale). - Symptoms of the common cold in the 24-hour period before administration of study medication were to be listed. Safety: Adverse events had to be recorded throughout the study. Statistical methods: The study was conducted using a three-stage group sequential test design according to Wang and Tsiatis [7]. For confirmatory testing of H 0 in the interim analyses as well as in the final analysis the two-

6 Summary and conclusions: Summary of efficacy: sample t-test was applied. It was tested, whether the 6-hour SPID of sore throat pain is identical (H 0 ) in the treatment arms A (ASA 1000 mg) and B (paracetamol 1000 mg). The criterion for significance (α) had been set equal to The test was one-sided, which means that only an effect in the expected direction was interpreted. The alternative hypothesis (H 1 ) was that the 6-hour SPID of sore throat pain is larger in the ASA than in the paracetamol treatment group. H 0 was to be rejected according to the result of the two-sample t-test. All items recorded in the CRF were analysed by means of descriptive statistical methods. Whenever appropriate, standard summary statistics were calculated. Categorical data (e.g. gender, ethnic origin) were summarized in frequency tables. All items were analyzed by treatment group. The primary efficacy variable was the sum of pain intensity differences compared to baseline over a period of 6 h (SPID 0-6 ). In the final analysis, only exploratory comparisons could be applied, because the confirmatory testing was completed with the negative result of the first interim analysis when it was decided not to continue with the study according to the sequential group design. In the ITT data set SPID 0-6 was slightly higher in the ASA group (25.0 ± 18.4 [21.5]) than in the paracetamol and placebo group (24.2 ± 18.8 [20.0] and 21.7 ± 15.9 [18.5]). However, the differences between treatments groups were minor, and exploratory comparison of the SPID 0-6 between the ASA and paracetamol group showed no statistically relevant difference in the final analysis (p = , two-sample t-test, one-sided). Unexpectedly, no effect of ASA vs. placebo and no effect of paracetamol vs. placebo was found as well (p = and p = , respectively, two-sample t-test, one sided). Mean PID values were slightly higher in the ASA than in paracetamol group during the first 240 min post-dose. Both active treatment groups showed consistently higher PID scores compared to placebo during that period. As a consequence, after administration of the study medication the mean SPID 0-2 (6.5 ± 5.0 [6.0], 6.3 ± 5.7 [5.0] and 4.7 ± 4.4 [4.0] in the ASA, paracetamol and placebo group) and mean SPID 0-4 (16.4 ± 11.6 [14.0], 15.7 ± 12.0 [13.0] and 12.8 ± 9.9 [11.0], respectively) displayed the same order between the treatment groups as the SPID 0-6. Pain relief was rated on a 7-category verbal scale (no -, slight -, mild -, moderate -, considerable -, almost complete -, complete relief associated with a scale from 0 to 6, respectively). All treatment groups showed a similar score at the various time points. The ASA group showed only marginally higher mean scores of pain relief during the first

7 240 min post-dose compared to the paracetamol and placebo group. Both active groups showed only marginally better scores than placebo. In analogy to the calculation of the SPID, the variable TOTPAR was calculated as the sum of all preceding pain relief assessments from 0.5 h post-dose to the last included assessment. TOTPAR 0-2 amounted to 6.1 ± 4.2 [6.0], 5.7 ± 4.2 [5.0] and 5.0 ± 3.7 [4.0] in the ASA, paracetamol and placebo group. TOTPAR 0-4 amounted to 14.0 ± 9.4 [13.0], 13.0 ± 9.2 [11.0] and 11.8 ± 8.1 [9.5], respectively, whereas TOTPAR 0-6 amounted to 20.9 ± 14.8 [18.0], 19.6 ± 14.3 [17.0] and 19.6 ± 13.5 [18.0] in the ASA, paracetamol and placebo group. Despite the marginal differences between treatment groups in pain relief at the various time points, the sum of the pain relief assessments after 2, 4, and 6 h consistently produced the same ranking ASA > paracetamol > placebo. During the 2 hours inpatient period after intake of study medication, the URTI symptoms headache, sinus pressure/pain, feverish discomfort as well as muscle aches and pain were assessed. The intensity of the symptom was scaled from 0 (not at all) to 10 (very much). In general but not always consistently, the active treatments ASA and paracetamol led to a stronger reduction of symptoms than placebo: At baseline, the mean intensity of headache amounted to 4.5 ± 2.8 [5.0], 4.6 ± 3.0 [5.0] and 4.7 ± 2.9 [6.0] in the ASA, paracetamol and placebo group 2 h post-dose, the mean headache intensity decreased by 1.2 ± 2.0 [1.0], 0.9 ± 2.1 [1.0] and 1.0 ± 2.2 [1.0], respectively. At baseline, the mean intensity of sinus pressure/pain amounted to 4.4 ± 3.0 [5.0], 4.5 ± 3.0 [5.0] and 4.7 ± 3.1 [5.0] in the ASA, paracetamol and placebo group. 2 h post-dose, the mean sinus pressure/pain intensity decreased by 1.1 ± 2.1 [1.0], 1.0 ± 1.8 [0.0] and 0.9 ± 1.5 [1.0], respectively. At baseline, the mean intensity of feverish discomfort amounted to 3.7 ± 3.0 [4.0], 3.9 ± 3.1 [4.0] and 4.1 ± 3.1 [5.0] in the ASA, paracetamol and placebo group. 2 h post-dose, the mean feverish discomfort intensity decreased by 1.0 ± 2.1 [1.0], 1.2 ± 1.9 [1.0] and 1.1 ± 1.4 [1.0], respectively. At baseline, the mean intensity of muscle aches and pains amounted to 4.3 ± 3.1 [5.0], 4.6 ± 2.9 [5.0] and 4.4 ± 3.1 [5.0] in the ASA, paracetamol and placebo group. 2 h postdose, the mean intensity of muscle aches and pains decreased by 1.2 ± 1.8 [1.0], 1.2 ± 1.8 [1.0] and 1.0 ± 1.5 [1.0], respectively. The results for the PP analysis were in line with those obtained from the ITT data set, this applied also to the failure to demonstrate a statistically relevant difference in SPID 0-6 in favor of the ASA group compared to the paracetamol group (p = , two-sample t-test, one-sided).

8 Summary of safety: No serious adverse events were observed after single doses of 1000 mg ASA, 1000 mg paracetamol or placebo. The vast majority of AEs was of mild or moderate intensity, whereas only 1/206 patients (0.5 %) in the ASA group (cough) and 1/100 patients (1.0 %) in the placebo group (headache) experienced AEs of severe intensity. The rate of patients with AEs was higher in the placebo group (14/100 patients (14.0 %) than in the verum groups (16/206 (7.8 %) and 15/202 (7.4 %) patients in the ASA and paracetamol group). The majority of AEs in the placebo group was obviously related to the cold and comprised among others 2/100 patients (2.0 %) with dizziness, 2/100 patients (2.0 %) with headache, and one patient each with back pain, ear pain, eye pain, as well as glossodynia. The system organ class (SOC) most frequently affected by AEs was the gastrointestinal system (8/206 (3.9 %) 8/202 (4.0 %) and 5/100 (5.0 %) patients in the ASA, paracetamol and placebo group). Following in frequency were nervous system disorders (4/206 (1.9 %) 5/202 (2.5 %) and 6/100 (6.0 %) patients, respectively). Adverse events with possible relationship to the study medication were observed in 11/206 (5.3 %) 8/202 (4.0 %) and 5/100 (5.0 %) patients after ASA, paracetamol and placebo treatment. This concerned most frequently patients with nausea (3/206 (1.5 %) 3/202 (1.5 %) and 2/100 (2.0 %) patients, respectively). The majority of patients with AEs required no action in response to an AE and their AEs resolved until the end of study. Conclusions: Single doses of 1000 mg ASA or 1000 mg paracetamol were safe and well tolerated. In general, severity and frequency of AEs were low and comparable between test drug, comparator and placebo. The efficacy hypothesis of ASA being superior over paracetamol regarding the primary efficacy variable SPID0-6 was not proven (p = , two-sample t-test, one sided). Moreover, no effect of ASA vs. placebo and no effect of paracetamol vs. placebo was found as well (p = and p = , respectively, two-sample t-test, one sided).