- Email: [email protected]
Upper gastrointestinal tolerability of alendronate sodium monohydrate 10 mg once daily in postmenopausal women: A 12-week, randomized, double-blind, placebo-controlled, exploratory study
Clinical Therapeutics/Volume 31, Number 8, 2009
Brief Report
Upper Gastrointestinal Tolerability of Alendronate Sodium Monohydrate 10 mg Once Daily in Postmenopausal Women: A 12-Week, Randomized, Double-Blind, Placebo-Controlled, Exploratory Study Jonathan D. Adachi, MD, FRCPC1; Rafat Y. Faraawi, MD, FRCPC2; Michael F.J. O’Mahony, MD3; Arun Nayar, MD4; Rachid Massaad, PhD5; Judith K. Evans, MD5; and Carol Yacik, BS5 1McMaster
University, Hamilton, Ontario, Canada; 2St. Mary’s General Hospital, Belmont Professional Centre, Kitchener, Ontario, Canada; 3London Road Diagnostic Clinic, Sarnia, Ontario, Canada; 4Royal University Hospital, Saskatoon, Saskatchewan, Canada; and 5Merck Research Laboratories, Rahway, New Jersey ABSTRACT Background: The dissolution profiles of generic oral bisphosphonate alendronate (ALN) sodium for the treatment of postmenopausal osteoporosis differ by formulation, suggesting potential differences in the risk for upper gastrointestinal (GI) irritation. Objective: This study compared the tolerability profile of ALN monohydrate with that of placebo, with a focus on upper GI irritation, in postmenopausal women with osteoporosis. Methods: This multicenter, double-blind, placebocontrolled estimation study enrolled postmenopausal women with osteoporosis. Patients were randomized in a 2:1 ratio to receive ALN monohydrate 10 mg or placebo once daily for 12 weeks. Tolerability was monitored throughout the study and up to 14 days after administration of the final dose. Primary end points were the proportions of patients with upper GI adverse events (AEs); upper GI AEs that were rated as serious or study drug related or that led to study discontinuation; and esophageal AEs. Between-treatment differences and associated 95% CIs were assessed using the Wilson score method. Results: Of 438 patients who were randomized, 367 (mean age, 65.5 years; history of osteoporotic fracture, 6.8%; ALN monohydrate, 237; placebo, 130) completed the study. The proportion of patients with a history of upper GI disorders at baseline was numerically greater in the ALN monohydrate group than in the placebo group (117 [40.2%] and 45 [30.6%], August 2009
respectively). The proportions of patients with active baseline upper GI disease were 83 (28.5%) and 30 (20.4%) in the ALN monohydrate and placebo groups, respectively. The proportions of patients who experienced an upper GI AE during the study period were 66 (22.7%) and 30 (20.4%) (95% CI, –6.2 to 10.0). The proportions of patients with upper GI AEs that were rated as serious or study drug related or that led to study discontinuation were 20.3% and 12.9% (95% CI, –0.3% to 14.1%). Three serious AEs in the active-treatment group (breast cancer, 2; wrist fracture, 1) were not considered related to the study drug, nor was the 1 serious AE in the placebo group (wrist fracture). One patient (ALN monohydrate) had an esophageal AE (nonserious spasm). Approximately 8% of patients who received ALN monohydrate reported dyspepsia, compared with none who received placebo. Within each treatment group, the rates of upper GI AEs were numerically higher in patients with a history of upper GI disease. Conclusions: In these postmenopausal women who received ALN monohydrate or placebo, upper GI AEs were common (20.4%–22.7%). The proportion of patients who experienced upper GI AEs considered drug related or that led to discontinuation was apparAccepted for publication August 7, 2009. doi:10.1016/j.clinthera.2009.08.016 0149-2918/$ - see front matter © 2009 Excerpta Medica Inc. All rights reserved.
1747
Clinical Therapeutics ently greater with ALN monohydrate compared with placebo. (Clin Ther. 2009;31:1747–1753) © 2009 Excerpta Medica Inc. Key words: alendronate, bisphosphonate, osteoporosis, esophagitis, tolerability, postmenopausal, upper GI.
and the lack of sufficient data for the estimation of events of interest, such as esophageal and upper GI AEs, it was not possible to make accurate assumptions for the calculations of sample size and power necessary to the design of a hypothesis-testing trial. Therefore, this trial was designed as an estimation study.
INTRODUCTION
MATERIALS AND METHODS Study Design
Osteoporosis is common in Canada, with evidence of vertebral fractures observed in 20% to 25% of the general population aged >50 years.1 Despite the availability of a number of therapeutic options, patients with fragility fracture might not undergo osteoporosis management and thus are at a high risk for subsequent fractures. In an attempt to increase the access to osteoporosis treatments, generic bisphosphonates were developed. Oral bisphosphonates, known to be poorly absorbed in the gastrointestinal (GI) tract, have been associated with an increased risk for esophageal/upper GI adverse events (AEs), especially when administered incorrectly, compared with earlier osteoporosis treatments.2,3 The prevalence of upper GI AEs reported with the use of a branded formulation of bisphosphonate, alendronate (ALN) sodium,* was reported to be similar to that of placebo in controlled clinical trials in patients with osteoporosis.4,5 However, the GI tolerability of generic formulations has not been studied as extensively and is unclear.6,7 Because certain AEs, in particular esophageal irritation, might result from events that occur prior to the absorption of the drug into the GI tract, it has been postulated that the length of time required for a given formulation to disintegrate and dissolve may impact the risk for the drug to cause irritation.6 In vitro studies of various generic formulations of ALN have found variations in disintegration and dissolution profiles as well as a potential for esophageal bioadhesion and have suggested that these differences may influence bioavailability, pharmacokinetics, efficacy, and tolerability.6,8 The present study was designed to compare the upper GI tolerability of ALN monohydrate† with that of placebo in postmenopausal women with osteoprosis. Due to the limited information available on the tolerability profile of the ALN monohydrate formulation *Trademark: Fosamax® (Merck & Co., Inc., Rahway, New Jersey). †Manufacturer: Novopharm Ltd. (Markham, Ontario, Canada).
1748
The study (protocol 239) was conducted at 34 centers in Canada and Colombia, from January 21, 2005, through June 23, 2005. Each center’s ethics review committee approved the study protocol, and all patients provided written informed consent attesting to their understanding of the study procedures, awareness of alternative treatments for osteoporosis, and willingness to participate in the study before any study procedures were performed.
Patients and Procedures Eligible patients were postmenopausal women (at least 6 months after their last menstrual period) and at least 40 years of age (or ≥25 years if surgically menopausal). Patients were included if they had either a history of osteoporotic fracture or a bone mineral density <2.0 SDs below the mean for young adults, as assessed using dual-energy X-ray absorptiometry performed within 3 years before randomization. Patients were required to have an adequate intake of vitamin D and calcium through diet and/or supplements, as determined by the study investigator based on information obtained during the screening process. Patients were randomly assigned to 1 of 2 treatment groups using a computer-generated randomization schedule created by the sponsor. Supplies were provided with one sealed envelope containing drugdisclosure information for each allocation number. Disclosure envelopes were received by a designated person at the study site and stored in a secured location to which only the investigator and designated assistants had access in the case of an emergency. Patients, investigators, and their staff remained blinded to treatment allocation throughout the study and afterward until the clinical study report was completed by the sponsor. Patients were assigned in a 2:1 ratio to receive oral ALN monohydrate 10 mg or matching placebo once daily for 12 weeks. AEs, particularly those pertaining to the upper GI system, were monitored throughout Volume 31 Number 8
J.D. Adachi et al. the study and up to 14 days after administration of the final dose. The estimations of primary interest were the percentages of patients in each group who experienced esophageal AEs, and upper GI AEs that were determined by the investigator to be serious or study drug related or that led to study discontinuation. Overall tolerability was also assessed.
Statistical Methods The sponsor managed data and performed the analyses based on a data-analysis plan established prior to study start, and data were unblinded after locking of the database. All allocated patients who took at least 1 dose of study medication were included in the tolerability analysis. Between-treatment differences in the tolerability variables of interest were presented with their associated 95% CIs derived from the Wilson score method. Therefore, the 95% CIs should be regarded as a helpful descriptive measure rather than a formal method of assessing the statistical significance of between-group differences in AEs. The influence of the factors (age, history of upper GI disease, and frequent use [cumulative use for >15 days during the 12-week study period] of aspirin/NSAIDs) on treatment effect was assessed using a logistic model with terms for treatment, country, factor of interest, and the treatment-by-factor interaction. Based on results from previously published alendronate trials, assuming that <0.7% of patients in the placebo group experienced an esophageal AE versus ~4.0% in the ALN monohydrate group, with 400 patients randomized in a 2:1 ratio (ALN monohydrate vs placebo), the 95% CI for the difference in percentages was 0.5% to 6.8% (precision estimate, ~3.0%).4,5 With respect to upper GI AEs, assuming incidence rates of 15% and 25% in the placebo and ALN monohydrate groups, respectively, the sample size provided a 95% CI for the difference in percentages equal to 1.2% to 17.3%. Because this was a tolerability study, all patients who received study treatment were included in the analyses.
RESULTS A total of 438 patients were randomized (291 in the ALN monohydrate group and 147 in the placebo group), and 367 patients completed the study (mean age, 65.5 years; history of osteoporotic fracture, 6.8%; ALN monohydrate, 237; placebo, 130). The August 2009
figure shows the disposition of patients, and baseline characteristics of the study population are shown in Table I. Patients ranged in age from 28.0 to 95.0 years. Among patients randomized, ~28% in each treatment group were frequent aspirin/NSAID users (ie, cumulative use for >15 days during the 12-week study period). The proportions of patients who had a history of upper GI disorders (117/291 [40.2%] vs 45/147 [30.6%]), esophageal disease (22/291 [7.6%] vs 5/147 [3.4%]), and/or active upper GI disease (83/291 [28.5%] vs 30/147 [20.4%]) at baseline were slightly higher in the ALN monohydrate group compared with the placebo group. A summary of AEs is shown in Table II. In general, rates of AEs were similar between groups, although the proportion of patients who had study drug–related AEs and/or who discontinued due to an AE was numerically greater in the ALN monohydrate group than in the placebo group. There were no serious upper GI AEs in either treatment group. No deaths or laboratory AEs were reported in the study. Among the 4 serious AEs that occurred among patients who received ALN monohydrate, 1 (diverticulitis) was considered possibly related to the study drug, and treatment was discontinued. The other 3 serious AEs in the activetreatment group (breast cancer, 2; wrist fracture, 1) were not considered related to the study drug, nor was the 1 serious AE in the placebo group (wrist fracture). The proportions of patients who experienced an upper GI AE during the study period were 66 of 291 (22.7%) with ALN monohydrate and 30 of 147 (20.4%) with placebo (95% CI, –6.2% to 10.0%) (Table II). Upper GI AEs that were rated as serious or study drug related or that led to study discontinuation occurred at rates of 20.3% in the ALN monohydrate group and 12.9% in the placebo group (treatment difference, 7.4%; 95% CI, –0.3% to 14.1%). One of these events was a nonserious upper GI bleed diagnosed based on the presence of melena, which was attributed to study drug use and led to study withdrawal. In the ALN monohydrate group, 7.9% of patients (23/291) experienced dyspepsia, whereas none of the patients in the placebo group reported this symptom. One patient in the ALN monohydrate group had an esophageal spasm that was attributed to the study drug but did not result in discontinuation from the study. In the ALN monohydrate group, upper GI AEs occurred in 26.5% (31/117) of patients with a history of upper GI disease, compared with 1749
Clinical Therapeutics
Screened (N = 672) Not randomized (n = 234) Ineligible (234) Randomized (2:1) (n = 438)
ALN monohydrate (n = 291)
Placebo (n = 147)
Discontinued (n = 54) Clinical adverse event (39) Withdrew consent (6) Lost to follow-up (3) Protocol deviation (3) Other (3)
Discontinued (n = 17) Clinical adverse event (14) Withdrew consent (3)
Completed study (n = 237)
Completed study (n = 130)
Included in efficacy analysis (n = 291)
Included in efficacy analysis (n = 147)
Figure. Patient disposition. ALN = alendronate.
20.1% (35/174) of patients without a history of the disease (95% CI, –3.3 to 16.5). Likewise, in the placebo group, upper GI AEs occurred in 28.9% (13/45) of patients with a history of upper GI disease, compared with 16.7% (17/102) of patients without such a history (95% CI, –1.8 to 27.9). For upper GI AEs, a significant interaction was noted between treatment and frequent use of aspirin/ NSAIDs. Among NSAID users, 23.5% (19/81) of patients who received ALN monohydrate reported upper GI AEs, compared with 34.1% (14/41) who received placebo. In contrast, among patients who were not frequent NSAID users, 22.4% (47/210) of patients who received ALN monohydrate reported upper GI AEs, compared with 15.1% (16/106) who received placebo. 1750
DISCUSSION Although several generic versions of ALN are commercially available, not all of these formulations have been fully characterized in terms of therapeutic equivalence or tolerability profile relative to the branded drug. Of particular relevance is the upper GI tolerability of the various formulations, as bisphosphonates in general might cause GI irritation, and treatments may need to be individualized, as one generic formulation may cause upper GI problems in a patient whereas another does not. To investigate the tolerability profile of one of these formulations (ALN monohydrate), the active drug was compared with placebo in this randomized estimation study. The proportion of patients who experienced drug-related upper GI AEs was nuVolume 31 Number 8
J.D. Adachi et al.
Table I. Baseline demographic and clinical characteristics of the study population.
Characteristic
ALN Monohydrate (n = 291)
Placebo (n = 147)
Age, y Mean (SD) Median Range
65.4 (10.5) 66.0 28.0–90.0
65.7 (9.9) 65.0 43.0–95.0
Age group, no. (%) <65 years ≥65 years
141 (48.5) 150 (51.5)
71 (48.3) 76 (51.7)
Race/ethnicity, no. (%) White Hispanic Asian Black
256 (88.0) 24 (8.2) 8 (2.7) 3 (1.0)
132 (89.8) 12 (8.2) 3 (2.0) 0
Risk factors, no. (%) T-score <–2.0 History of upper GI disease Active upper GI disease Frequent aspirin/NSAID use* History of esophageal disease History of osteoporotic fracture
283 (97.3) 117 (40.2) 83 (28.5) 81 (27.8) 22 (7.6) 18 (6.2)
146 (99.3) 45 (30.6) 30 (20.4) 41 (27.9) 5 (3.4) 12 (8.2)
ALN = alendronate sodium; GI = gastrointestinal. *Defined as cumulative use for >15 days during the 12-week study period.
merically greater in the ALN monohydrate group compared with the placebo group, and of the patients who reported dyspepsia, all were in the active-treatment group. Although a difference in baseline history of upper GI disorders was noted, there was no apparent difference in either group in rates of upper GI AEs between patients with a history of upper GI disease and those without such a history. The rates at which generic formulations of ALN disintegrate and dissolve vary, and it has been suggested that this variation may correlate with variations in GI tolerability.3,6 Several examples of mechanisms by which a causal relationship may exist have been posited,6 including the supposition that rapid disintegration could increase oral and esophageal mucosal exposure to active drug, thereby increasing the likelihood of irritation. Conversely, characteristics such as tablet shape and coating may delay esophageal tranAugust 2009
sit and increase the risk for pill esophagitis, which may in turn be exacerbated by a longer disintegration/ dissolution time.6 However, studies that have directly assessed the potential associations between variable dissolution profiles and degree of gastric irritation are scarce. By comparing the risks for upper GI irritation associated with the use of a generic formulation versus placebo, the present study may help to answer questions about the impact these physical properties of the tablets may have on upper GI tolerability of formulations of ALN. There were limitations to this study. This study used a placebo, rather than an active drug, as the comparator, making it easier to detect between-treatment differences. The use of an active comparator would have required a much larger study. Because an active comparator was not included, it is unknown whether the prevalences of GI AEs that were reported with the 1751
Clinical Therapeutics
Table II. Clinical and gastrointestinal (GI) adverse events (AEs) of primary interest, based on an all-patients-treated approach. Values are no. (%) of patients. ALN Monohydrate (n = 291)
Placebo (n = 147)
Any AE Drug-related AE* Serious AE Serious drug-related AE Death
166 (57.0) 87 (29.9) 4 (1.4)† 1 (0.3) 0
76 (51.7) 35 (23.8) 1 (0.7)‡ 0 0
Reason for discontinuation Any AE Drug-related AE* Serious AE Serious drug-related AE
38 (13.1) 31 (10.7) 2 (0.7) 1 (0.3)
14 (9.5) 11 (7.5) 0 0
66 (22.7)
30 (20.4)
59 (20.3) 1 (0.3)
19 (12.9) 0
Parameter
AEs of interest§ Upper GI Upper GI rated as serious or drug related, or that led to study discontinuation Esophageal
* Determined by the investigator to be possibly, probably, or definitely drug related. † Included breast cancer (2 patients; unrelated to study drug), diverticulitis (1 patient; possibly related to study drug), and wrist fracture (1 patient; unrelated to study drug). ‡ Wrist fracture (1 patient; unrelated to study drug). § Estimated treatment differences (95% CI) for esophageal, upper GI, upper GI rated as serious or drug related or that led to study discontinuation: 0%, 2.3% (–6.2% to 10.0% [nonsignificant]), and 7.3% (–0.3% to 14.1% [nonsignificant]), respectively (Wilson score method).
use of ALN monohydrate were higher than those of any other formulation, including the branded ALN or generic formulations. Also, the results presented here for a single generic ALN formulation do not necessarily apply to other generic formulations. This was an estimation study; thus, no hypotheses were tested. The between-group differences in estimates and the 95% CIs were assessed descriptively using the Wilson score method, which does not provide any matching test-based P value. Therefore, the 95% CIs should be regarded as a helpful descriptive measure rather than a formal method of assessing the statistical significance of between-group differences in AEs. The study was designed to provide a sufficient estimate of the risk for upper GI AEs relative to placebo, and the findings may be useful in guiding the designs of future studies. 1752
CONCLUSIONS In these postmenopausal women, upper GI AEs were common with both ALN monohydrate and placebo (20.4%–22.7%). The proportion of patients who experienced upper GI AEs considered drug related or that led to discontinuation was apparently greater with ALN monohydrate than with placebo.
ACKNOWLEDGMENTS Financial support for this research and its publication was provided by Merck & Co., Inc., Rahway, New Jersey, the manufacturer of Fosamax. The authors thank Drs. Antonio Lombardi and Carolyn Hustad, Merck, for assistance with editing and subsequent revision of the manuscript. Drs. Adachi, Faraawi, O’Mahony, and Nayar have received funding from Merck for clinical studies and/ Volume 31 Number 8
J.D. Adachi et al. or have acted as consultants or speakers for Merck. Dr. Massaad, Ms. Yacik, and Dr. Evans are employees of Merck and may hold stock options in the company. Dr. Adachi has received consultant’s fees from, been a member of the speakers’ bureau of, or participated in clinical trials for Amgen Canada Inc., AstraZeneca Pharmaceuticals LP, Eli Lilly Canada Inc., GlaxoSmithKline, Merck, Novartis Pharmaceuticals Corporation, Pfizer Inc., Procter and Gamble Pharmaceuticals, Roche Diagnostics Corp, sanofi-aventis Canada Inc., Servier, and Wyeth Pharmaceuticals.
4.
5.
6.
REFERENCES 1. Jackson SA, Tenenhouse A, Robertson L. Vertebral fracture definition from population-based data: Preliminary results from the Canadian Multicenter Osteoporosis Study (CaMos). Osteoporos Int. 2000;11:680–687. 2. Cryer B, Bauer DC. Oral bisphosphonates and upper gastrointestinal tract problems: What is the evidence? Mayo Clin Proc. 2002;77:1031–1043. 3. Epstein S, Geusens P, Fisher JE, et al. Disintegration and esophageal irritation profiles of alendronate formulations:
7.
8.
Implications for clinical safety and efficacy. J Appl Res. 2005;5:253–265. Watts N, Freedholm D, Daifotis A. The clinical tolerability profile of alendronate. Int J Clin Pract Suppl. 1999;101:51– 61. Eisman JA, Rizzoli R, Roman-Ivorra J, et al. Upper gastrointestinal and overall tolerability of alendronate once weekly in patients with osteoporosis: Results of a randomized, double-blind, placebo-controlled study [published correction appears in Curr Med Res Opin. 2004;20:575]. Curr Med Res Opin. 2004;20:699–705. Epstein S, Cryer B, Ragi S, et al. Disintegration/dissolution profiles of copies of Fosamax (alendronate) [published correction appears in Curr Med Res Opin. 2004;20:575]. Curr Med Res Opin. 2003;19:781–789. Halkin H, Dushenat M, Silverman B, et al. Brand versus generic alendronate: Gastrointestinal effects measured by resource utilization. Ann Pharmacother. 2007;41:29– 34. Shakweh M, Bravo-Osuna I, Ponchel G. Comparative in vitro study of oesophageal adhesiveness of different commercial formulations containing alendronate. Eur J Pharm Sci. 2007;31:262–270.
Address correspondence to: Jonathan D. Adachi, MD, FRCPC, Charlton Medical Centre, 501-25 Charlton Avenue East, Hamilton, ON L8N 1Y2, Canada. E-mail: [email protected] August 2009
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Brief Report
Upper Gastrointestinal Tolerability of Alendronate Sodium Monohydrate 10 mg Once Daily in Postmenopausal Women: A 12-Week, Randomized, Double-Blind, Placebo-Controlled, Exploratory Study Jonathan D. Adachi, MD, FRCPC1; Rafat Y. Faraawi, MD, FRCPC2; Michael F.J. O’Mahony, MD3; Arun Nayar, MD4; Rachid Massaad, PhD5; Judith K. Evans, MD5; and Carol Yacik, BS5 1McMaster
University, Hamilton, Ontario, Canada; 2St. Mary’s General Hospital, Belmont Professional Centre, Kitchener, Ontario, Canada; 3London Road Diagnostic Clinic, Sarnia, Ontario, Canada; 4Royal University Hospital, Saskatoon, Saskatchewan, Canada; and 5Merck Research Laboratories, Rahway, New Jersey ABSTRACT Background: The dissolution profiles of generic oral bisphosphonate alendronate (ALN) sodium for the treatment of postmenopausal osteoporosis differ by formulation, suggesting potential differences in the risk for upper gastrointestinal (GI) irritation. Objective: This study compared the tolerability profile of ALN monohydrate with that of placebo, with a focus on upper GI irritation, in postmenopausal women with osteoporosis. Methods: This multicenter, double-blind, placebocontrolled estimation study enrolled postmenopausal women with osteoporosis. Patients were randomized in a 2:1 ratio to receive ALN monohydrate 10 mg or placebo once daily for 12 weeks. Tolerability was monitored throughout the study and up to 14 days after administration of the final dose. Primary end points were the proportions of patients with upper GI adverse events (AEs); upper GI AEs that were rated as serious or study drug related or that led to study discontinuation; and esophageal AEs. Between-treatment differences and associated 95% CIs were assessed using the Wilson score method. Results: Of 438 patients who were randomized, 367 (mean age, 65.5 years; history of osteoporotic fracture, 6.8%; ALN monohydrate, 237; placebo, 130) completed the study. The proportion of patients with a history of upper GI disorders at baseline was numerically greater in the ALN monohydrate group than in the placebo group (117 [40.2%] and 45 [30.6%], August 2009
respectively). The proportions of patients with active baseline upper GI disease were 83 (28.5%) and 30 (20.4%) in the ALN monohydrate and placebo groups, respectively. The proportions of patients who experienced an upper GI AE during the study period were 66 (22.7%) and 30 (20.4%) (95% CI, –6.2 to 10.0). The proportions of patients with upper GI AEs that were rated as serious or study drug related or that led to study discontinuation were 20.3% and 12.9% (95% CI, –0.3% to 14.1%). Three serious AEs in the active-treatment group (breast cancer, 2; wrist fracture, 1) were not considered related to the study drug, nor was the 1 serious AE in the placebo group (wrist fracture). One patient (ALN monohydrate) had an esophageal AE (nonserious spasm). Approximately 8% of patients who received ALN monohydrate reported dyspepsia, compared with none who received placebo. Within each treatment group, the rates of upper GI AEs were numerically higher in patients with a history of upper GI disease. Conclusions: In these postmenopausal women who received ALN monohydrate or placebo, upper GI AEs were common (20.4%–22.7%). The proportion of patients who experienced upper GI AEs considered drug related or that led to discontinuation was apparAccepted for publication August 7, 2009. doi:10.1016/j.clinthera.2009.08.016 0149-2918/$ - see front matter © 2009 Excerpta Medica Inc. All rights reserved.
1747
Clinical Therapeutics ently greater with ALN monohydrate compared with placebo. (Clin Ther. 2009;31:1747–1753) © 2009 Excerpta Medica Inc. Key words: alendronate, bisphosphonate, osteoporosis, esophagitis, tolerability, postmenopausal, upper GI.
and the lack of sufficient data for the estimation of events of interest, such as esophageal and upper GI AEs, it was not possible to make accurate assumptions for the calculations of sample size and power necessary to the design of a hypothesis-testing trial. Therefore, this trial was designed as an estimation study.
INTRODUCTION
MATERIALS AND METHODS Study Design
Osteoporosis is common in Canada, with evidence of vertebral fractures observed in 20% to 25% of the general population aged >50 years.1 Despite the availability of a number of therapeutic options, patients with fragility fracture might not undergo osteoporosis management and thus are at a high risk for subsequent fractures. In an attempt to increase the access to osteoporosis treatments, generic bisphosphonates were developed. Oral bisphosphonates, known to be poorly absorbed in the gastrointestinal (GI) tract, have been associated with an increased risk for esophageal/upper GI adverse events (AEs), especially when administered incorrectly, compared with earlier osteoporosis treatments.2,3 The prevalence of upper GI AEs reported with the use of a branded formulation of bisphosphonate, alendronate (ALN) sodium,* was reported to be similar to that of placebo in controlled clinical trials in patients with osteoporosis.4,5 However, the GI tolerability of generic formulations has not been studied as extensively and is unclear.6,7 Because certain AEs, in particular esophageal irritation, might result from events that occur prior to the absorption of the drug into the GI tract, it has been postulated that the length of time required for a given formulation to disintegrate and dissolve may impact the risk for the drug to cause irritation.6 In vitro studies of various generic formulations of ALN have found variations in disintegration and dissolution profiles as well as a potential for esophageal bioadhesion and have suggested that these differences may influence bioavailability, pharmacokinetics, efficacy, and tolerability.6,8 The present study was designed to compare the upper GI tolerability of ALN monohydrate† with that of placebo in postmenopausal women with osteoprosis. Due to the limited information available on the tolerability profile of the ALN monohydrate formulation *Trademark: Fosamax® (Merck & Co., Inc., Rahway, New Jersey). †Manufacturer: Novopharm Ltd. (Markham, Ontario, Canada).
1748
The study (protocol 239) was conducted at 34 centers in Canada and Colombia, from January 21, 2005, through June 23, 2005. Each center’s ethics review committee approved the study protocol, and all patients provided written informed consent attesting to their understanding of the study procedures, awareness of alternative treatments for osteoporosis, and willingness to participate in the study before any study procedures were performed.
Patients and Procedures Eligible patients were postmenopausal women (at least 6 months after their last menstrual period) and at least 40 years of age (or ≥25 years if surgically menopausal). Patients were included if they had either a history of osteoporotic fracture or a bone mineral density <2.0 SDs below the mean for young adults, as assessed using dual-energy X-ray absorptiometry performed within 3 years before randomization. Patients were required to have an adequate intake of vitamin D and calcium through diet and/or supplements, as determined by the study investigator based on information obtained during the screening process. Patients were randomly assigned to 1 of 2 treatment groups using a computer-generated randomization schedule created by the sponsor. Supplies were provided with one sealed envelope containing drugdisclosure information for each allocation number. Disclosure envelopes were received by a designated person at the study site and stored in a secured location to which only the investigator and designated assistants had access in the case of an emergency. Patients, investigators, and their staff remained blinded to treatment allocation throughout the study and afterward until the clinical study report was completed by the sponsor. Patients were assigned in a 2:1 ratio to receive oral ALN monohydrate 10 mg or matching placebo once daily for 12 weeks. AEs, particularly those pertaining to the upper GI system, were monitored throughout Volume 31 Number 8
J.D. Adachi et al. the study and up to 14 days after administration of the final dose. The estimations of primary interest were the percentages of patients in each group who experienced esophageal AEs, and upper GI AEs that were determined by the investigator to be serious or study drug related or that led to study discontinuation. Overall tolerability was also assessed.
Statistical Methods The sponsor managed data and performed the analyses based on a data-analysis plan established prior to study start, and data were unblinded after locking of the database. All allocated patients who took at least 1 dose of study medication were included in the tolerability analysis. Between-treatment differences in the tolerability variables of interest were presented with their associated 95% CIs derived from the Wilson score method. Therefore, the 95% CIs should be regarded as a helpful descriptive measure rather than a formal method of assessing the statistical significance of between-group differences in AEs. The influence of the factors (age, history of upper GI disease, and frequent use [cumulative use for >15 days during the 12-week study period] of aspirin/NSAIDs) on treatment effect was assessed using a logistic model with terms for treatment, country, factor of interest, and the treatment-by-factor interaction. Based on results from previously published alendronate trials, assuming that <0.7% of patients in the placebo group experienced an esophageal AE versus ~4.0% in the ALN monohydrate group, with 400 patients randomized in a 2:1 ratio (ALN monohydrate vs placebo), the 95% CI for the difference in percentages was 0.5% to 6.8% (precision estimate, ~3.0%).4,5 With respect to upper GI AEs, assuming incidence rates of 15% and 25% in the placebo and ALN monohydrate groups, respectively, the sample size provided a 95% CI for the difference in percentages equal to 1.2% to 17.3%. Because this was a tolerability study, all patients who received study treatment were included in the analyses.
RESULTS A total of 438 patients were randomized (291 in the ALN monohydrate group and 147 in the placebo group), and 367 patients completed the study (mean age, 65.5 years; history of osteoporotic fracture, 6.8%; ALN monohydrate, 237; placebo, 130). The August 2009
figure shows the disposition of patients, and baseline characteristics of the study population are shown in Table I. Patients ranged in age from 28.0 to 95.0 years. Among patients randomized, ~28% in each treatment group were frequent aspirin/NSAID users (ie, cumulative use for >15 days during the 12-week study period). The proportions of patients who had a history of upper GI disorders (117/291 [40.2%] vs 45/147 [30.6%]), esophageal disease (22/291 [7.6%] vs 5/147 [3.4%]), and/or active upper GI disease (83/291 [28.5%] vs 30/147 [20.4%]) at baseline were slightly higher in the ALN monohydrate group compared with the placebo group. A summary of AEs is shown in Table II. In general, rates of AEs were similar between groups, although the proportion of patients who had study drug–related AEs and/or who discontinued due to an AE was numerically greater in the ALN monohydrate group than in the placebo group. There were no serious upper GI AEs in either treatment group. No deaths or laboratory AEs were reported in the study. Among the 4 serious AEs that occurred among patients who received ALN monohydrate, 1 (diverticulitis) was considered possibly related to the study drug, and treatment was discontinued. The other 3 serious AEs in the activetreatment group (breast cancer, 2; wrist fracture, 1) were not considered related to the study drug, nor was the 1 serious AE in the placebo group (wrist fracture). The proportions of patients who experienced an upper GI AE during the study period were 66 of 291 (22.7%) with ALN monohydrate and 30 of 147 (20.4%) with placebo (95% CI, –6.2% to 10.0%) (Table II). Upper GI AEs that were rated as serious or study drug related or that led to study discontinuation occurred at rates of 20.3% in the ALN monohydrate group and 12.9% in the placebo group (treatment difference, 7.4%; 95% CI, –0.3% to 14.1%). One of these events was a nonserious upper GI bleed diagnosed based on the presence of melena, which was attributed to study drug use and led to study withdrawal. In the ALN monohydrate group, 7.9% of patients (23/291) experienced dyspepsia, whereas none of the patients in the placebo group reported this symptom. One patient in the ALN monohydrate group had an esophageal spasm that was attributed to the study drug but did not result in discontinuation from the study. In the ALN monohydrate group, upper GI AEs occurred in 26.5% (31/117) of patients with a history of upper GI disease, compared with 1749
Clinical Therapeutics
Screened (N = 672) Not randomized (n = 234) Ineligible (234) Randomized (2:1) (n = 438)
ALN monohydrate (n = 291)
Placebo (n = 147)
Discontinued (n = 54) Clinical adverse event (39) Withdrew consent (6) Lost to follow-up (3) Protocol deviation (3) Other (3)
Discontinued (n = 17) Clinical adverse event (14) Withdrew consent (3)
Completed study (n = 237)
Completed study (n = 130)
Included in efficacy analysis (n = 291)
Included in efficacy analysis (n = 147)
Figure. Patient disposition. ALN = alendronate.
20.1% (35/174) of patients without a history of the disease (95% CI, –3.3 to 16.5). Likewise, in the placebo group, upper GI AEs occurred in 28.9% (13/45) of patients with a history of upper GI disease, compared with 16.7% (17/102) of patients without such a history (95% CI, –1.8 to 27.9). For upper GI AEs, a significant interaction was noted between treatment and frequent use of aspirin/ NSAIDs. Among NSAID users, 23.5% (19/81) of patients who received ALN monohydrate reported upper GI AEs, compared with 34.1% (14/41) who received placebo. In contrast, among patients who were not frequent NSAID users, 22.4% (47/210) of patients who received ALN monohydrate reported upper GI AEs, compared with 15.1% (16/106) who received placebo. 1750
DISCUSSION Although several generic versions of ALN are commercially available, not all of these formulations have been fully characterized in terms of therapeutic equivalence or tolerability profile relative to the branded drug. Of particular relevance is the upper GI tolerability of the various formulations, as bisphosphonates in general might cause GI irritation, and treatments may need to be individualized, as one generic formulation may cause upper GI problems in a patient whereas another does not. To investigate the tolerability profile of one of these formulations (ALN monohydrate), the active drug was compared with placebo in this randomized estimation study. The proportion of patients who experienced drug-related upper GI AEs was nuVolume 31 Number 8
J.D. Adachi et al.
Table I. Baseline demographic and clinical characteristics of the study population.
Characteristic
ALN Monohydrate (n = 291)
Placebo (n = 147)
Age, y Mean (SD) Median Range
65.4 (10.5) 66.0 28.0–90.0
65.7 (9.9) 65.0 43.0–95.0
Age group, no. (%) <65 years ≥65 years
141 (48.5) 150 (51.5)
71 (48.3) 76 (51.7)
Race/ethnicity, no. (%) White Hispanic Asian Black
256 (88.0) 24 (8.2) 8 (2.7) 3 (1.0)
132 (89.8) 12 (8.2) 3 (2.0) 0
Risk factors, no. (%) T-score <–2.0 History of upper GI disease Active upper GI disease Frequent aspirin/NSAID use* History of esophageal disease History of osteoporotic fracture
283 (97.3) 117 (40.2) 83 (28.5) 81 (27.8) 22 (7.6) 18 (6.2)
146 (99.3) 45 (30.6) 30 (20.4) 41 (27.9) 5 (3.4) 12 (8.2)
ALN = alendronate sodium; GI = gastrointestinal. *Defined as cumulative use for >15 days during the 12-week study period.
merically greater in the ALN monohydrate group compared with the placebo group, and of the patients who reported dyspepsia, all were in the active-treatment group. Although a difference in baseline history of upper GI disorders was noted, there was no apparent difference in either group in rates of upper GI AEs between patients with a history of upper GI disease and those without such a history. The rates at which generic formulations of ALN disintegrate and dissolve vary, and it has been suggested that this variation may correlate with variations in GI tolerability.3,6 Several examples of mechanisms by which a causal relationship may exist have been posited,6 including the supposition that rapid disintegration could increase oral and esophageal mucosal exposure to active drug, thereby increasing the likelihood of irritation. Conversely, characteristics such as tablet shape and coating may delay esophageal tranAugust 2009
sit and increase the risk for pill esophagitis, which may in turn be exacerbated by a longer disintegration/ dissolution time.6 However, studies that have directly assessed the potential associations between variable dissolution profiles and degree of gastric irritation are scarce. By comparing the risks for upper GI irritation associated with the use of a generic formulation versus placebo, the present study may help to answer questions about the impact these physical properties of the tablets may have on upper GI tolerability of formulations of ALN. There were limitations to this study. This study used a placebo, rather than an active drug, as the comparator, making it easier to detect between-treatment differences. The use of an active comparator would have required a much larger study. Because an active comparator was not included, it is unknown whether the prevalences of GI AEs that were reported with the 1751
Clinical Therapeutics
Table II. Clinical and gastrointestinal (GI) adverse events (AEs) of primary interest, based on an all-patients-treated approach. Values are no. (%) of patients. ALN Monohydrate (n = 291)
Placebo (n = 147)
Any AE Drug-related AE* Serious AE Serious drug-related AE Death
166 (57.0) 87 (29.9) 4 (1.4)† 1 (0.3) 0
76 (51.7) 35 (23.8) 1 (0.7)‡ 0 0
Reason for discontinuation Any AE Drug-related AE* Serious AE Serious drug-related AE
38 (13.1) 31 (10.7) 2 (0.7) 1 (0.3)
14 (9.5) 11 (7.5) 0 0
66 (22.7)
30 (20.4)
59 (20.3) 1 (0.3)
19 (12.9) 0
Parameter
AEs of interest§ Upper GI Upper GI rated as serious or drug related, or that led to study discontinuation Esophageal
* Determined by the investigator to be possibly, probably, or definitely drug related. † Included breast cancer (2 patients; unrelated to study drug), diverticulitis (1 patient; possibly related to study drug), and wrist fracture (1 patient; unrelated to study drug). ‡ Wrist fracture (1 patient; unrelated to study drug). § Estimated treatment differences (95% CI) for esophageal, upper GI, upper GI rated as serious or drug related or that led to study discontinuation: 0%, 2.3% (–6.2% to 10.0% [nonsignificant]), and 7.3% (–0.3% to 14.1% [nonsignificant]), respectively (Wilson score method).
use of ALN monohydrate were higher than those of any other formulation, including the branded ALN or generic formulations. Also, the results presented here for a single generic ALN formulation do not necessarily apply to other generic formulations. This was an estimation study; thus, no hypotheses were tested. The between-group differences in estimates and the 95% CIs were assessed descriptively using the Wilson score method, which does not provide any matching test-based P value. Therefore, the 95% CIs should be regarded as a helpful descriptive measure rather than a formal method of assessing the statistical significance of between-group differences in AEs. The study was designed to provide a sufficient estimate of the risk for upper GI AEs relative to placebo, and the findings may be useful in guiding the designs of future studies. 1752
CONCLUSIONS In these postmenopausal women, upper GI AEs were common with both ALN monohydrate and placebo (20.4%–22.7%). The proportion of patients who experienced upper GI AEs considered drug related or that led to discontinuation was apparently greater with ALN monohydrate than with placebo.
ACKNOWLEDGMENTS Financial support for this research and its publication was provided by Merck & Co., Inc., Rahway, New Jersey, the manufacturer of Fosamax. The authors thank Drs. Antonio Lombardi and Carolyn Hustad, Merck, for assistance with editing and subsequent revision of the manuscript. Drs. Adachi, Faraawi, O’Mahony, and Nayar have received funding from Merck for clinical studies and/ Volume 31 Number 8
J.D. Adachi et al. or have acted as consultants or speakers for Merck. Dr. Massaad, Ms. Yacik, and Dr. Evans are employees of Merck and may hold stock options in the company. Dr. Adachi has received consultant’s fees from, been a member of the speakers’ bureau of, or participated in clinical trials for Amgen Canada Inc., AstraZeneca Pharmaceuticals LP, Eli Lilly Canada Inc., GlaxoSmithKline, Merck, Novartis Pharmaceuticals Corporation, Pfizer Inc., Procter and Gamble Pharmaceuticals, Roche Diagnostics Corp, sanofi-aventis Canada Inc., Servier, and Wyeth Pharmaceuticals.
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Implications for clinical safety and efficacy. J Appl Res. 2005;5:253–265. Watts N, Freedholm D, Daifotis A. The clinical tolerability profile of alendronate. Int J Clin Pract Suppl. 1999;101:51– 61. Eisman JA, Rizzoli R, Roman-Ivorra J, et al. Upper gastrointestinal and overall tolerability of alendronate once weekly in patients with osteoporosis: Results of a randomized, double-blind, placebo-controlled study [published correction appears in Curr Med Res Opin. 2004;20:575]. Curr Med Res Opin. 2004;20:699–705. Epstein S, Cryer B, Ragi S, et al. Disintegration/dissolution profiles of copies of Fosamax (alendronate) [published correction appears in Curr Med Res Opin. 2004;20:575]. Curr Med Res Opin. 2003;19:781–789. Halkin H, Dushenat M, Silverman B, et al. Brand versus generic alendronate: Gastrointestinal effects measured by resource utilization. Ann Pharmacother. 2007;41:29– 34. Shakweh M, Bravo-Osuna I, Ponchel G. Comparative in vitro study of oesophageal adhesiveness of different commercial formulations containing alendronate. Eur J Pharm Sci. 2007;31:262–270.
Address correspondence to: Jonathan D. Adachi, MD, FRCPC, Charlton Medical Centre, 501-25 Charlton Avenue East, Hamilton, ON L8N 1Y2, Canada. E-mail: [email protected] August 2009
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