Current Medical Research & Opinion 0300-7995 doi:10.1185/03007995.2014.925437
Vol. 30, No. 9, 2014, 1863–1870
Article ST-0024.R1/925437 All rights reserved: reproduction in whole or part not permitted
Curr Med Res Opin Downloaded from informahealthcare.com by University of Guelph on 12/27/14 For personal use only.
Original article Etoricoxib in the treatment of primary dysmenorrhea in Chinese patients: a randomized controlled trial
Qi Yu Xiaqin Zhu Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
Xiaowei Zhang Department of Gynecology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
Yi Zhang Department of Obstetrics and Gynecology, Beijing Hospital, Beijing, China
Xiaomao Li Qi Hua Department of Gynecology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
Qing Chang Department of Obstetrics and Gynecology, Southwest Hospital, The Third Military Medical University, Chongqing, China
Qindi Zou Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
Wen Di Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Abstract Objective: Assess the efficacy and safety of etoricoxib 120 mg compared with ibuprofen 600 mg qid in the treatment of moderate to severe primary dysmenorrhea in Chinese women. Methods: This multicenter, double-blind, two-period, cross-over study randomized healthy, Chinese women 18 years of age to etoricoxib 120 mg qd or ibuprofen up to 2400 mg (600 mg qid) upon onset of moderate or severe primary dysmenorrhea symptoms during two menstrual cycles. The primary efficacy endpoint was Total Pain Relief score over the first 6 hours (TOPAR6). Secondary endpoints included Sum of Pain Intensity Difference scores over the first 6 hours (SPID6) and Patient’s Global Evaluation (GLOBAL) of pain at 6 and 24 hours post initial dose. The primary hypothesis was that etoricoxib would be non-inferior to ibuprofen. Adverse experiences (AE) were monitored and evaluated. Results: A total of 139 patients were included in this study. Difference in least squares (LS) mean (95% CI) TOPAR6 score for etoricoxib vs. ibuprofen was 0.89 (0.03, 1.76) (p ¼ 0.043). LS mean (95% CI) difference for etoricoxib vs. ibuprofen SPID6, GLOBAL6, and GLOBAL24 were 0.20 (1.16, 1.57) (p ¼ 0.768), 0.26 (0.07, 0.45) (p ¼ 0.007), and 0.36 (0.17, 0.54) (p50.001), respectively. AEs were rare, with the following AEs determined to be drug-related: hypomenorrhea (two patients on etoricoxib) and allergic dermatitis (one patient on ibuprofen). Limitations of the study design include a sample size that is not adequate for evaluation of rare adverse effects, an evaluation period that was limited to 24 hours, and inconsistent frequency of active treatment doses between etoricoxib (once daily) and ibuprofen (up to four times daily). Conclusions: The primary objective of the study was met, demonstrating that etoricoxib 120 mg qd was non-inferior to ibuprofen 600 mg qid; further, etoricoxib was statistically superior to ibuprofen 600 mg qid according to the primary endpoint (TOPAR6) and patient global assessments of study medication. Etoricoxib and ibuprofen were generally well tolerated.
Yuanqing Yao Department of Obstetrics and Gynecology, Chinese PLA General Hospital, Beijing, China
Wenbo Yu Ji Liu Anish Mehta Li Yan Merck & Co. Inc., Whitehouse Station, NJ, USA
! 2014 Informa UK Ltd www.cmrojournal.com
Introduction Primary dysmenorrhea is a common gynecological problem that involves pain during menstruation without demonstrable underlying pathology. It is prevalent in up to 50–90% of menstruating women and can cause significant economic and social impact through absenteeism and through interference with daily activities1,2. During menstruation, disintegrating endometrial cells release prostaglandin E (PGE) and prostaglandin F2a (PGF2a), thus stimulating uterine Etoricoxib for dysmenorrhea in Chinese women Yu et al.
1863
Current Medical Research & Opinion Volume 30, Number 9
Address for correspondence: Li Yan MD PhD, Merck & Co. Inc., 351 North Sumneytown Pike, North Wales, PA 19454, USA. Tel.: +1 267 305 0545; [email protected] Key words: Chinese women – Etoricoxib – Ibuprofen – Noninferior – Primary dysmenorrhea – TOPAR6
Curr Med Res Opin Downloaded from informahealthcare.com by University of Guelph on 12/27/14 For personal use only.
Accepted: 14 May 2014; published online: 30 June 2014 Citation: Curr Med Res Opin 2014; 30:1863–70
September 2014
muscle contractions and shedding of the endometrium. In addition to stimulating muscle contractions, PGF2a and PGE also result in ischemia and sensitization of nerve endings3,4. Furthermore, women who have severe dysmenorrhea have been shown to have higher levels of the prostaglandins in their menstrual fluid compared with women who experience normal menstruation5. In the treatment of dysmenorrhea, pharmacologic interventions that inhibit the production of prostaglandins, such as non-selective non-steroidal antiinflammatory drugs (NSAIDs) and cyclooxygenase-2 (COX-2) selective inhibitors, have demonstrated significant pain relief6. Etoricoxib is a COX-2 selective inhibitor that has previously demonstrated efficacy in the treatment of several painful conditions including primary dysmenorrhea in Western study populations7,8. Although a number of treatment options exist, inter-individual variability in treatment effect with regard to both efficacy and safety from analgesics has been observed, which can be addressed by the availability of several treatment options9,10. Etoricoxib has demonstrated the onset of efficacy in some patients in less than 30 minutes and a single dose has a duration of over 24 hours11. These analgesic properties may be beneficial to Chinese patients, but evidence from clinical trials are needed to confirm that genetic and ethnic variability does not have an effect on the treatment outcomes with etoricoxib in a Chinese or Asian population. This randomized, controlled study was conducted in order to assess the efficacy and safety of etoricoxib 120 mg compared with the traditional NSAID, ibuprofen 600 mg qid, in the treatment of moderate to severe primary dysmenorrhea in Chinese women. We hypothesized that etoricoxib 120 mg qd would be non-inferior to ibuprofen 600 mg qid in this population of Chinese women with primary dysmenorrhea.
Methods This study (Sponsor Protocol 145, Clinical Trials Registry # NCT01462370) was conducted in 10 sites in China from December 2011 to June 2012. The study was approved by local Ethics Review Committees. All women provided written informed consent before any study procedure was performed and provided updated written informed consent upon protocol changes. This study was conducted according to principles of Good Clinical Practice.
Study design This was a multicenter, randomized, double-blind, active-comparator-controlled, two-period, cross-over study in patients with primary dysmenorrhea. Patients were randomly allocated to two possible sequences of the two treatment regimens to be administered over the course of two menstrual cycles. A study coordinator ensured that data was being collected correctly. A computer-generated allocation schedule was used to randomize patients to treatments. Inhouse blinding procedures were used where allocation of study drugs was concealed to patients, investigator site staff, laboratory personnel, and the sponsor throughout the trial. Patients were given blinded kits that contained four bottles: bottles A (etoricoxib 120 mg or matching placebo) and B (ibuprofen 600 mg or matching placebo) were used during cycle 1 and bottles C (etoricoxib 120 mg or matching placebo) and D (ibuprofen 600 mg or matching placebo) were used during cycle 2. Additional medication to be taken on an as-needed basis (up to an additional three doses) were provided; placebo was used for the additional two etoricoxib doses to match the maximum daily dose of ibuprofen allowed in this study (i.e., 2400 mg). The assignment code was revealed once recruitment, data 1864
Etoricoxib for dysmenorrhea in Chinese women Yu et al.
www.cmrojournal.com ! 2014 Informa UK Ltd
Curr Med Res Opin Downloaded from informahealthcare.com by University of Guelph on 12/27/14 For personal use only.
Current Medical Research & Opinion Volume 30, Number 9
collection, and laboratory analyses were completed and the study database was locked. The cross-over design allowed patients to be assigned two possible sequences: etoricoxib in menstrual cycle 1 and ibuprofen in menstrual cycle 2 or ibuprofen in menstrual cycle 1 and etoricoxib in menstrual cycle 2. Upon onset of moderate-to-severe pain, patients took their first dose of study medication (etoricoxib 120 mg or ibuprofen 600 mg); subsequent doses of study medication (placebo for the etoricoxib treatment and ibuprofen 600 mg for the ibuprofen treatment) could be taken every 6 hours or longer, up to four times a day if needed. Study medications (etoricoxib 120 mg or ibuprofen 600 mg) were taken only during the first 24 hours after onset of moderate-to-severe pain in each menstrual cycle. During the 24 hours following the first dose of study medication, patients recorded pain intensity and pain relief assessments in a diary at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 20, and 24 hours post initial dose. Patients provided a global assessment of the study medication received for pain relief at 6 and 24 hours post-dose. Rescue medication (Saridon [isopropylantipyrine 150 mg, acetaminophen 250 mg, anhydrous caffeine 50 mg]) was provided for uncontrolled pain, but patients were instructed to refrain from using rescue medication during the first 90 minutes after each administration of study medication. No study medication was taken after the patient took the first dose of rescue medication. Patients who took rescue medication during menstrual cycle 1 participated as scheduled in menstrual cycle 2. At visit 1 eligible patients were screened and at visit 2 patients were randomized to study treatments. At visits 3 and 4, the investigator or study coordinator reviewed the diary. At visit 4, a physical examination was performed and blood/urine samples for safety laboratories were collected. If visit 4 occurred 514 days post-dose, a follow-up telephone call after 14 days post-dose was made to assess for the occurrence of adverse experiences.
Patients Patients were women 18 years of age with moderate to severe primary dysmenorrhea during four or more of the previous six menstrual cycles. Diagnosis of primary dysmenorrhea was determined by medical history and physical examination (including a complete gynecological exam) by the investigators. Moderate primary dysmenorrhea was diagnosed if discomfort interferes with usual activity and over-the-counter analgesics provide significant relief. Severe primary dysmenorrhea was diagnosed if discomfort is incapacitating and over-the-counter analgesics are not consistently effective or prescription analgesics are required. Patients were to demonstrate that they were not pregnant, were not breastfeeding, and were not ! 2014 Informa UK Ltd www.cmrojournal.com
September 2014
56 weeks postpartum, and agreed to either remain abstinent or use two methods for contraception during the study. Patients were to refrain from concurrent therapy that could interfere with study evaluations. Patients were excluded if they had a disease or abnormality of the reproductive organs or used an intrauterine device. Patients were also excluded if they had a history of a significant clinical or laboratory event that would contraindicate therapy with study or rescue medication or if patients had an allergy to NSAIDs or COX-2 inhibitors or rescue medication.
Efficacy endpoints The primary endpoint in this study was Total Pain Relief over the first 6 hours post-dose (TOPAR6). Secondary endpoints included Sum of Pain Intensity Difference (PID) scores over the 6 hour time period post-dose (SPID6) and Patient’s Global Evaluation of study medication for pain at 6 and 24 hours post initial dose. Additional secondary and tertiary endpoints included time to PID 1 unit during 6 hours post-dose, time to rescue medication, peak PID during 6 hours post-dose, peak pain relief (PR) during 6 hours post-dose, PID and PR at 12 and 24 hours post-dose, proportion of patients with good to excellent patient’s global evaluation of study medication at 6 and 24 hours, TOPAR 24, and SPID 24.
Safety endpoints During the study, we evaluated change from baseline in vital sign parameters (i.e., heart rate, blood pressure, temperature, and respiration rate) and change or percentage change from baseline in laboratory safety parameters at the end of the study. Clinical and laboratory adverse experiences were reported during each of the treatment periods. Laboratory tests included complete blood count (CBC), serum chemistry panel, urinalysis, serum hCG, and urine hCG. The following safety parameters in particular were recorded: Any AEs with incidence 4 patients in a treatment group, serious AEs; drug-related AEs, and serious drugrelated AEs; AEs that resulted in discontinuations.
Statistical analyses The primary hypothesis tested in this trial was that etoricoxib was considered noninferior to ibuprofen; noninferiority of etoricoxib to ibuprofen was established if the lower bound of the two-sided 95% confidence interval (CI) of the between-treatment difference in the least squares (LS) means was not smaller than 3.7 units. The primary analysis used the per-protocol (PP) population (all randomized patients without Etoricoxib for dysmenorrhea in Chinese women Yu et al.
1865
Curr Med Res Opin Downloaded from informahealthcare.com by University of Guelph on 12/27/14 For personal use only.
Current Medical Research & Opinion Volume 30, Number 9
September 2014
important protocol deviations). The full analysis set (FAS) included all patients who received 1 dose of study treatment and had a baseline measurement and 1 observation post-dose. For all analyses of pain relief, pain intensity, and Patient’s Global Evaluation of study medication for pain, measurements obtained after the first dose of rescue medication was treated as missing. The last-observationcarried-forward (LOCF) method was employed to impute these missing values within the specific period. However, data from the first period were not carried forward to the second period. Missing data due to other reasons were handled similarly. The study was designed to include 128 patients (64 in each treatment sequence), with which it would be estimated that the study would have 92% power (overall one-sided 2.5% alpha-level) to establish that etoricoxib 120 mg is noninferior to ibuprofen 600 mg for TOPAR6. These estimates are based on prior primary dysmenorrhea studies with etoricoxib7. For the primary endpoint, an analysis of variance model (ANOVA) was used with terms for treatment, period, sequence, patient, and baseline pain intensity as factors. The secondary endpoints were analyzed by ANOVA (nominal P-values and 95% CI for between-group differences were calculated). Time-to-event endpoints used the Cox proportional hazards regression model and Kaplan–Meier product
limit estimates. For continuous endpoints, nominal P-values and 95% CI were calculated to evaluate between-treatment differences. The safety analysis used the all patients-as-treated (APaT) population, which included all patients who received 1 dose in 1 treatment cycle. Point estimates with 95% CIs for between-group comparisons (McNemar Test) were calculated. No multiplicity adjustments were made.
Results Patient accounting and demographics There were 139 randomized patients with 133 (95.7%) who completed the study; of the six patients who did not complete the study, five patients did not take any study medication (two patients did not have a qualifying event, two patients withdrew and one patient was discontinued due to physician decision), one patient in treatment sequence 2 (ibuprofen up to 2400 mg/etoricoxib 120 mg) withdrew consent after completing the first cycle (Figure 1). The number of patients taking rescue medication was relatively low. During the first 6 hours, one
Screened N=156
5 subjects discontinued before administration of study medication Reasons for discontinuation: Withdrew consent = 2 Lack of qualifying event = 2 Physician decision = 1
Randomized N=139
Reasons for not being randomized: Disease or abnormality of reproductive organs = 10 Clinically significant laboratory abnormality = 4 Did not provide consent = 3 Patient was judged to not be in good health = 3 Patient was
Vol. 30, No. 9, 2014, 1863–1870
Article ST-0024.R1/925437 All rights reserved: reproduction in whole or part not permitted
Curr Med Res Opin Downloaded from informahealthcare.com by University of Guelph on 12/27/14 For personal use only.
Original article Etoricoxib in the treatment of primary dysmenorrhea in Chinese patients: a randomized controlled trial
Qi Yu Xiaqin Zhu Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
Xiaowei Zhang Department of Gynecology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
Yi Zhang Department of Obstetrics and Gynecology, Beijing Hospital, Beijing, China
Xiaomao Li Qi Hua Department of Gynecology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
Qing Chang Department of Obstetrics and Gynecology, Southwest Hospital, The Third Military Medical University, Chongqing, China
Qindi Zou Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
Wen Di Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Abstract Objective: Assess the efficacy and safety of etoricoxib 120 mg compared with ibuprofen 600 mg qid in the treatment of moderate to severe primary dysmenorrhea in Chinese women. Methods: This multicenter, double-blind, two-period, cross-over study randomized healthy, Chinese women 18 years of age to etoricoxib 120 mg qd or ibuprofen up to 2400 mg (600 mg qid) upon onset of moderate or severe primary dysmenorrhea symptoms during two menstrual cycles. The primary efficacy endpoint was Total Pain Relief score over the first 6 hours (TOPAR6). Secondary endpoints included Sum of Pain Intensity Difference scores over the first 6 hours (SPID6) and Patient’s Global Evaluation (GLOBAL) of pain at 6 and 24 hours post initial dose. The primary hypothesis was that etoricoxib would be non-inferior to ibuprofen. Adverse experiences (AE) were monitored and evaluated. Results: A total of 139 patients were included in this study. Difference in least squares (LS) mean (95% CI) TOPAR6 score for etoricoxib vs. ibuprofen was 0.89 (0.03, 1.76) (p ¼ 0.043). LS mean (95% CI) difference for etoricoxib vs. ibuprofen SPID6, GLOBAL6, and GLOBAL24 were 0.20 (1.16, 1.57) (p ¼ 0.768), 0.26 (0.07, 0.45) (p ¼ 0.007), and 0.36 (0.17, 0.54) (p50.001), respectively. AEs were rare, with the following AEs determined to be drug-related: hypomenorrhea (two patients on etoricoxib) and allergic dermatitis (one patient on ibuprofen). Limitations of the study design include a sample size that is not adequate for evaluation of rare adverse effects, an evaluation period that was limited to 24 hours, and inconsistent frequency of active treatment doses between etoricoxib (once daily) and ibuprofen (up to four times daily). Conclusions: The primary objective of the study was met, demonstrating that etoricoxib 120 mg qd was non-inferior to ibuprofen 600 mg qid; further, etoricoxib was statistically superior to ibuprofen 600 mg qid according to the primary endpoint (TOPAR6) and patient global assessments of study medication. Etoricoxib and ibuprofen were generally well tolerated.
Yuanqing Yao Department of Obstetrics and Gynecology, Chinese PLA General Hospital, Beijing, China
Wenbo Yu Ji Liu Anish Mehta Li Yan Merck & Co. Inc., Whitehouse Station, NJ, USA
! 2014 Informa UK Ltd www.cmrojournal.com
Introduction Primary dysmenorrhea is a common gynecological problem that involves pain during menstruation without demonstrable underlying pathology. It is prevalent in up to 50–90% of menstruating women and can cause significant economic and social impact through absenteeism and through interference with daily activities1,2. During menstruation, disintegrating endometrial cells release prostaglandin E (PGE) and prostaglandin F2a (PGF2a), thus stimulating uterine Etoricoxib for dysmenorrhea in Chinese women Yu et al.
1863
Current Medical Research & Opinion Volume 30, Number 9
Address for correspondence: Li Yan MD PhD, Merck & Co. Inc., 351 North Sumneytown Pike, North Wales, PA 19454, USA. Tel.: +1 267 305 0545; [email protected] Key words: Chinese women – Etoricoxib – Ibuprofen – Noninferior – Primary dysmenorrhea – TOPAR6
Curr Med Res Opin Downloaded from informahealthcare.com by University of Guelph on 12/27/14 For personal use only.
Accepted: 14 May 2014; published online: 30 June 2014 Citation: Curr Med Res Opin 2014; 30:1863–70
September 2014
muscle contractions and shedding of the endometrium. In addition to stimulating muscle contractions, PGF2a and PGE also result in ischemia and sensitization of nerve endings3,4. Furthermore, women who have severe dysmenorrhea have been shown to have higher levels of the prostaglandins in their menstrual fluid compared with women who experience normal menstruation5. In the treatment of dysmenorrhea, pharmacologic interventions that inhibit the production of prostaglandins, such as non-selective non-steroidal antiinflammatory drugs (NSAIDs) and cyclooxygenase-2 (COX-2) selective inhibitors, have demonstrated significant pain relief6. Etoricoxib is a COX-2 selective inhibitor that has previously demonstrated efficacy in the treatment of several painful conditions including primary dysmenorrhea in Western study populations7,8. Although a number of treatment options exist, inter-individual variability in treatment effect with regard to both efficacy and safety from analgesics has been observed, which can be addressed by the availability of several treatment options9,10. Etoricoxib has demonstrated the onset of efficacy in some patients in less than 30 minutes and a single dose has a duration of over 24 hours11. These analgesic properties may be beneficial to Chinese patients, but evidence from clinical trials are needed to confirm that genetic and ethnic variability does not have an effect on the treatment outcomes with etoricoxib in a Chinese or Asian population. This randomized, controlled study was conducted in order to assess the efficacy and safety of etoricoxib 120 mg compared with the traditional NSAID, ibuprofen 600 mg qid, in the treatment of moderate to severe primary dysmenorrhea in Chinese women. We hypothesized that etoricoxib 120 mg qd would be non-inferior to ibuprofen 600 mg qid in this population of Chinese women with primary dysmenorrhea.
Methods This study (Sponsor Protocol 145, Clinical Trials Registry # NCT01462370) was conducted in 10 sites in China from December 2011 to June 2012. The study was approved by local Ethics Review Committees. All women provided written informed consent before any study procedure was performed and provided updated written informed consent upon protocol changes. This study was conducted according to principles of Good Clinical Practice.
Study design This was a multicenter, randomized, double-blind, active-comparator-controlled, two-period, cross-over study in patients with primary dysmenorrhea. Patients were randomly allocated to two possible sequences of the two treatment regimens to be administered over the course of two menstrual cycles. A study coordinator ensured that data was being collected correctly. A computer-generated allocation schedule was used to randomize patients to treatments. Inhouse blinding procedures were used where allocation of study drugs was concealed to patients, investigator site staff, laboratory personnel, and the sponsor throughout the trial. Patients were given blinded kits that contained four bottles: bottles A (etoricoxib 120 mg or matching placebo) and B (ibuprofen 600 mg or matching placebo) were used during cycle 1 and bottles C (etoricoxib 120 mg or matching placebo) and D (ibuprofen 600 mg or matching placebo) were used during cycle 2. Additional medication to be taken on an as-needed basis (up to an additional three doses) were provided; placebo was used for the additional two etoricoxib doses to match the maximum daily dose of ibuprofen allowed in this study (i.e., 2400 mg). The assignment code was revealed once recruitment, data 1864
Etoricoxib for dysmenorrhea in Chinese women Yu et al.
www.cmrojournal.com ! 2014 Informa UK Ltd
Curr Med Res Opin Downloaded from informahealthcare.com by University of Guelph on 12/27/14 For personal use only.
Current Medical Research & Opinion Volume 30, Number 9
collection, and laboratory analyses were completed and the study database was locked. The cross-over design allowed patients to be assigned two possible sequences: etoricoxib in menstrual cycle 1 and ibuprofen in menstrual cycle 2 or ibuprofen in menstrual cycle 1 and etoricoxib in menstrual cycle 2. Upon onset of moderate-to-severe pain, patients took their first dose of study medication (etoricoxib 120 mg or ibuprofen 600 mg); subsequent doses of study medication (placebo for the etoricoxib treatment and ibuprofen 600 mg for the ibuprofen treatment) could be taken every 6 hours or longer, up to four times a day if needed. Study medications (etoricoxib 120 mg or ibuprofen 600 mg) were taken only during the first 24 hours after onset of moderate-to-severe pain in each menstrual cycle. During the 24 hours following the first dose of study medication, patients recorded pain intensity and pain relief assessments in a diary at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 20, and 24 hours post initial dose. Patients provided a global assessment of the study medication received for pain relief at 6 and 24 hours post-dose. Rescue medication (Saridon [isopropylantipyrine 150 mg, acetaminophen 250 mg, anhydrous caffeine 50 mg]) was provided for uncontrolled pain, but patients were instructed to refrain from using rescue medication during the first 90 minutes after each administration of study medication. No study medication was taken after the patient took the first dose of rescue medication. Patients who took rescue medication during menstrual cycle 1 participated as scheduled in menstrual cycle 2. At visit 1 eligible patients were screened and at visit 2 patients were randomized to study treatments. At visits 3 and 4, the investigator or study coordinator reviewed the diary. At visit 4, a physical examination was performed and blood/urine samples for safety laboratories were collected. If visit 4 occurred 514 days post-dose, a follow-up telephone call after 14 days post-dose was made to assess for the occurrence of adverse experiences.
Patients Patients were women 18 years of age with moderate to severe primary dysmenorrhea during four or more of the previous six menstrual cycles. Diagnosis of primary dysmenorrhea was determined by medical history and physical examination (including a complete gynecological exam) by the investigators. Moderate primary dysmenorrhea was diagnosed if discomfort interferes with usual activity and over-the-counter analgesics provide significant relief. Severe primary dysmenorrhea was diagnosed if discomfort is incapacitating and over-the-counter analgesics are not consistently effective or prescription analgesics are required. Patients were to demonstrate that they were not pregnant, were not breastfeeding, and were not ! 2014 Informa UK Ltd www.cmrojournal.com
September 2014
56 weeks postpartum, and agreed to either remain abstinent or use two methods for contraception during the study. Patients were to refrain from concurrent therapy that could interfere with study evaluations. Patients were excluded if they had a disease or abnormality of the reproductive organs or used an intrauterine device. Patients were also excluded if they had a history of a significant clinical or laboratory event that would contraindicate therapy with study or rescue medication or if patients had an allergy to NSAIDs or COX-2 inhibitors or rescue medication.
Efficacy endpoints The primary endpoint in this study was Total Pain Relief over the first 6 hours post-dose (TOPAR6). Secondary endpoints included Sum of Pain Intensity Difference (PID) scores over the 6 hour time period post-dose (SPID6) and Patient’s Global Evaluation of study medication for pain at 6 and 24 hours post initial dose. Additional secondary and tertiary endpoints included time to PID 1 unit during 6 hours post-dose, time to rescue medication, peak PID during 6 hours post-dose, peak pain relief (PR) during 6 hours post-dose, PID and PR at 12 and 24 hours post-dose, proportion of patients with good to excellent patient’s global evaluation of study medication at 6 and 24 hours, TOPAR 24, and SPID 24.
Safety endpoints During the study, we evaluated change from baseline in vital sign parameters (i.e., heart rate, blood pressure, temperature, and respiration rate) and change or percentage change from baseline in laboratory safety parameters at the end of the study. Clinical and laboratory adverse experiences were reported during each of the treatment periods. Laboratory tests included complete blood count (CBC), serum chemistry panel, urinalysis, serum hCG, and urine hCG. The following safety parameters in particular were recorded: Any AEs with incidence 4 patients in a treatment group, serious AEs; drug-related AEs, and serious drugrelated AEs; AEs that resulted in discontinuations.
Statistical analyses The primary hypothesis tested in this trial was that etoricoxib was considered noninferior to ibuprofen; noninferiority of etoricoxib to ibuprofen was established if the lower bound of the two-sided 95% confidence interval (CI) of the between-treatment difference in the least squares (LS) means was not smaller than 3.7 units. The primary analysis used the per-protocol (PP) population (all randomized patients without Etoricoxib for dysmenorrhea in Chinese women Yu et al.
1865
Curr Med Res Opin Downloaded from informahealthcare.com by University of Guelph on 12/27/14 For personal use only.
Current Medical Research & Opinion Volume 30, Number 9
September 2014
important protocol deviations). The full analysis set (FAS) included all patients who received 1 dose of study treatment and had a baseline measurement and 1 observation post-dose. For all analyses of pain relief, pain intensity, and Patient’s Global Evaluation of study medication for pain, measurements obtained after the first dose of rescue medication was treated as missing. The last-observationcarried-forward (LOCF) method was employed to impute these missing values within the specific period. However, data from the first period were not carried forward to the second period. Missing data due to other reasons were handled similarly. The study was designed to include 128 patients (64 in each treatment sequence), with which it would be estimated that the study would have 92% power (overall one-sided 2.5% alpha-level) to establish that etoricoxib 120 mg is noninferior to ibuprofen 600 mg for TOPAR6. These estimates are based on prior primary dysmenorrhea studies with etoricoxib7. For the primary endpoint, an analysis of variance model (ANOVA) was used with terms for treatment, period, sequence, patient, and baseline pain intensity as factors. The secondary endpoints were analyzed by ANOVA (nominal P-values and 95% CI for between-group differences were calculated). Time-to-event endpoints used the Cox proportional hazards regression model and Kaplan–Meier product
limit estimates. For continuous endpoints, nominal P-values and 95% CI were calculated to evaluate between-treatment differences. The safety analysis used the all patients-as-treated (APaT) population, which included all patients who received 1 dose in 1 treatment cycle. Point estimates with 95% CIs for between-group comparisons (McNemar Test) were calculated. No multiplicity adjustments were made.
Results Patient accounting and demographics There were 139 randomized patients with 133 (95.7%) who completed the study; of the six patients who did not complete the study, five patients did not take any study medication (two patients did not have a qualifying event, two patients withdrew and one patient was discontinued due to physician decision), one patient in treatment sequence 2 (ibuprofen up to 2400 mg/etoricoxib 120 mg) withdrew consent after completing the first cycle (Figure 1). The number of patients taking rescue medication was relatively low. During the first 6 hours, one
Screened N=156
5 subjects discontinued before administration of study medication Reasons for discontinuation: Withdrew consent = 2 Lack of qualifying event = 2 Physician decision = 1
Randomized N=139
Reasons for not being randomized: Disease or abnormality of reproductive organs = 10 Clinically significant laboratory abnormality = 4 Did not provide consent = 3 Patient was judged to not be in good health = 3 Patient was
