Mais les résultats doivent être attendus longtemps et il n'y a généralement pas de temps metronidazole prix L'autre cas, c'est que l'achat d'un ou d'un autre antibiotique dans une pharmacie classique nécessite des dépenses matérielles considérables et pas toutes les personnes ne peuvent acheter des produits pharmaceutiques aussi coûteux.

Doi:10.1016/j.maturitas.2003.12.012

Patients with osteoporosis prefer once weekly to David Kendler , Annie Wai Chee Kung , Ghada El-Hajj Fuleihan , José Gerardo González González , Keavy A. Gaines , a St. Vincent’s Hospital, 120-809 W 41 Avenue, Vancouver, BC, Canada V5Z 2N6 b Queen Mary Hospital, Hong Kong, PR China c American University of Beirut Medical Center, Beirut, Lebanon d Universidad Autónoma de Nuevo León, Monterey, Nuevo León, Mexico e Merck and Co. Inc., Whitehouse Station, NJ, USA f Merck Sharp and Dohme Inc. (Europe), Brussels, Belgium Received 17 July 2003; received in revised form 17 December 2003; accepted 17 December 2003 Abstract
Objectives: Once weekly dosing of alendronate has been shown to provide equivalent efficacy to once daily dosing for treatment of osteoporosis in postmenopausal women. Whether patients will prefer weekly dosing to daily dosing for a chroniccondition such as osteoporosis has not been studied. The aim of this international study was to assess preference for the weeklyor daily dosing regimen of alendronate among postmenopausal women with osteoporosis. Methods: This randomised open-labelcrossover study was conducted at 45 study sites in 19 countries. Four hundred and six postmenopausal women with osteoporosiswere assigned randomly to treatment with either alendronate 70 mg once weekly for 4 weeks followed by alendronate 10 mg oncedaily for 4 weeks or vice versa. The main outcome was the responses of the participants to the Dosing Regimen Questionnaireadministered at the end of the study. Results: Of the participants expressing a preference, 84% preferred the once weekly dosingregimen with alendronate to the once daily dosing regimen. In addition, the once weekly regimen was considered by 87% ofthe participants to be more convenient and was the regimen most of the participants (84%) would be more willing to take for along period of time (P < 0.001 for each parameter). Conclusions: The majority of postmenopausal women with osteoporosispreferred the once weekly to the once daily dosing regimen of alendronate. Physicians should consider patient preference fordosing regimen when selecting the appropriate treatment for osteoporosis.
2004 Elsevier Ireland Ltd. All rights reserved.
Keywords: Alendronate; Weekly; Preference; Osteoporosis ଝ This data has been presented in abstract form at the International Society of Clinical Densitometry Annual Meeting, Atlanta, GA, February 2002; the Fifth International Symposium: Clinical Advances in Osteoporosis, Honolulu, Hawaii, March 2002; The IOF WorldCongress on Osteoporosis, Lisbon, Portugal May 2002; the European League Against Rheumatism Annual Congress, Stockholm, Sweden,June 2002.
∗ Corresponding author. Tel.: +1-604-263-3644; fax: +1-604-263-3744.
E-mail address: [email protected] (D. Kendler).
0378-5122/$ – see front matter 2004 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.maturitas.2003.12.012 D. Kendler et al. / Maturitas 48 (2004) 243–251 1. Introduction
2. Methods
Low adherence and compliance with medications for chronic diseases is a well known problem. It hasbeen recognized that the full benefits of medications This was an open-label, randomised, crossover cannot be reached at current levels of compliance.
study of preference. This study was conducted at 45 Compliance with medical therapy for chronic diseases sites across 19 countries representative of Europe, is a complex and multifactorial problem, and requires Middle East, the Americas, and Asia-Pacific. Par- innovative solutions. Many attempts have been made ticipants were randomly assigned to treatment with to institute interventions to improve medication com- either alendronate (Fosamax®, Merck & Co. Inc., pliance. These interventions have been only modestly Whitehouse Station, NJ, USA) 10 mg once daily successful at best One of the most successful in- followed by treatment with alendronate 70 mg once terventions demonstrated to improve compliance is a weekly, or treatment with alendronate once weekly simplified dosing regimen. For example, it has been followed by alendronate once daily. Each dosing reg- shown that compliance improves as the number of imen was administered for 4 weeks, with a 1 week doses taken each day decreases Whether even off therapy period between dosing regimens. After less frequent dosing regimens, such as weekly dosing, experiencing both regimens, the participants com- would further improve compliance for chronic therapy is not known. Few medications for a treatment of a Ethics review committee approval was obtained for chronic disease are available in a once weekly formu- each site. Informed consent was obtained from all lation, and therefore little information is available on participants prior to performance of any study-related patient acceptance of a medication administered once Recently, taking advantage of pharmacokinetic properties, alendronate was developed for once weeklydosing for treatment and prevention of osteoporosis.
Postmenopausal women with osteoporosis (as The once weekly dosing regimen for alendronate determined by the investigator) were recruited was developed in an attempt to simplify the dosing from investigators’ practices and from media ad- regimen and potentially enhance compliance. Once vertisements. Participants were na¨ıve to thera- weekly dosing with alendronate has been shown to pies for osteoporosis, including bisphosphonates, provide equivalent efficacy to once daily dosing for calcitonin, and selective estrogen receptor mod- treatment of osteoporosis in postmenopausal women Patients are used to establishing a daily regimen and Vitamin D were allowed. Reasons to ex- to encourage them to remember to take their medi- clude women from the study included inability cations. Whether a once weekly regimen would be to follow alendronate dosing instructions, condi- easier to follow, or potentially more complicated and tions which delay esophageal emptying such as subject to greater inconvenience or missed doses, was stricture or achalasia, or a history of hypocal- cemia, hypoparathyroidism, osteomalacia, Paget’s In this study, we investigated the dosing prefer- disease or renal osteodystrophy. Other exclusions ence for alendronate given once daily or once weekly included uncontrolled moderate or severe hyper- among postmenopausal women with osteoporosis in a tension, new onset angina or myocardial infarc- randomized, open-label, cross-over designed, interna- tion within 6 months, impaired renal function, tional clinical trial. The participants were given the op- other significant end organ diseases, or cancer.
portunity to experience both once weekly alendronate Use of nonsteroidal antiinflammatory agents, H2 and once daily alendronate prior to saying which they antagonists, proton pump inhibitors, or a history prefer, which they think is more convenient, and which they would be more willing to continue over a long ders of esophageal motility) were not reasons for D. Kendler et al. / Maturitas 48 (2004) 243–251 DOSING REGIMEN QUESTIONNAIRE
You have just completed this study and have followed two different osteoporosis treatment routines: you have taken the osteoporosis medication once a week and you have taken it once a day. It is important to remember that the osteoporosis medications you took during these two treatment routines have the same beneficial effect for your bones. Please answer the three questions below. We encourage you to choose the answer that best describes your experience.
For each question, please check one box only
1. Which treatment routine do you prefer?
I prefer the once a week treatment routine I prefer the once a day treatment routine 2. Which treatment routine is more convenient?
The once a week treatment routine is more convenient The once a day treatment routine is more convenient The once a week treatment routine and the once a day treatment routine are equally convenient 3. Which treatment would you be more willing to take for a long
period of time?

I would be more willing to take the once a week treatment for a long period of time I would be more willing to take the once a day treatment for a long period of time I would be equally willing to take either the once a week or the once a day treatment for a long period of time Fig. 1. Dosing Regimen Questionnaire.
2.3. Treatment assignment and randomisation calcium and Vitamin D supplements according to thestandard of care in their communities. In addition, Allocation to treatment sequence was assigned ran- counseling for modification of lifestyle habits related domly using a computer-generated allocation sched- to osteoporosis, such as exercise, smoking cessation, ule. Open-label drug was provided for 4 weeks for and fall prevention, was encouraged.
each regimen (4 tablets of alendronate 70 mg onceweekly and 28 tablets of alendronate 10 mg once daily). For each regimen, the participants receivedthe standard dosing instructions for alendronate. For Participants returned for a randomisation visit for the once weekly regimen, the participants chose 1 initiation of the first treatment period and again when day of the week for the weekly dosing. Throughout switching to the second treatment period. All partic- the study, all participants were encouraged to take ipants were phoned on the day of initiation of study D. Kendler et al. / Maturitas 48 (2004) 243–251 drug (or up to 3 days after, in case of intervening hol- naire. The Mainland–Gart test for binary response in iday or weekend days) in each treatment period to en- a two-treatment, two-period crossover trial was used sure proper compliance to dosing instructions. After for this analysis The analyses of the responses experiencing both treatment regimens, participants re- to the other two questions on the questionnaire were turned for a final visit for completion of the Dosing handled in a similar fashion. As there was only one Regimen Questionnaire and collection of information primary endpoint (preference), there was no need for a multiplicity adjustment. The sample size estimationwas based on 90% power to detect a 20% difference 2.5. Questionnaire development and testing in preference with a 2-tailed test at a 5% significancelevel. At least 260 participants (130 per group) were The Dosing Regimen Questionnaire was designed required; additional participants were enrolled to al- to include the parameters of preference, convenience, low for those who would not complete the trial.
and willingness to continue taking the regimen long To assess the sequence effect of treatments, that term. In development of the questionnaire, in-depth is, to test whether the percentage of participants who interviews were conducted with women previously di- preferred alendronate 70 mg once weekly was the agnosed with osteoporosis, including those receiving same irrespective of the order in which the two treat- alendronate and those receiving other therapies for ment regimens have been given, the Mainland–Gart osteoporosis. These interviews were used to modify test was used, with a two-sided test at the 10% sig- the wording of the questions to ensure concept con- nificance level. To investigate the influence of various veyance and clarity before the questionnaire in English factors on preference for dosing regimen, analyses was finalised. Translation of the questionnaire into lo- by subgroup was performed. These analyses used a cal languages required at least two translations for logistic model on the preference of alendronate once each language, back-translations for each translation, weekly including the factor under consideration as a committee review, and pre-testing of the translated main effect to assess the consistency across the differ- questionnaire with non-study participants in the target ent subgroups. The following factors were considered: population of women with osteoporosis. This rigorous country of residence, age group (≤65, >65 years), procedure for translations was instituted to ensure that number of concomitant chronic medications (defined the original meaning and intent of the questionnaire as a medication taken for more than 75% of the time was preserved when a translation was required.
during the study), intake of at least one concomitant At the completion of the study, a short script was medication on more than 75% of the days in the study, read to each participant to introduce the questionnaire and number of active medical conditions at baseline.
and to explain that the participant is to complete the The adverse experiences were analysed for all par- questionnaire on her own, to the best of her ability, ticipants who took at least one dose of study med- without assistance from the investigator site staff. Par- ication for the treatment phase under consideration.
ticipants were informed that the two treatment regi- Also, a comparison of the overall adverse experience mens (alendronate 70 mg once weekly and alendronate reporting of the two treatment regimens was done us- 10 mg once daily) have equal benefit to bone so that ing the McNemar’s Test, which included only partici- their choice of regimen was not influenced by any pants who received at least one dose of each regimen.
perception of relative efficacy. Each participant com-pleted the questionnaire herself.
3. Results
3.1. Participants’ characteristics The primary analysis was the preference of partici- pants towards either of the two regimens. The analysis A total of 406 postmenopausal women with osteo- included all participants who took at least one dose porosis from 19 countries participated in the study.
from each regimen and expressed a preference based Sixty-five percent of the women reported their race on the first question of the Dosing Regimen Question- as Caucasian, 22% Asian, and 8% Hispanic. Regional D. Kendler et al. / Maturitas 48 (2004) 243–251 Number (%) with family history of osteoporosis Number (%) with caffeine use ≥3 cups per day diversity was also achieved with 92 (23%) of the par- the Asia-Pacific region. The baseline characteristics ticipants from North America, 57 (14%) from Central of the two treatment sequence groups were similar or South America, 104 (26%) from Europe, 54 (13%) (The most common active medical conditions from the Middle East and Africa and 99 (24%) from reported at baseline (other than osteoporosis) were Excluded, n=58 Entry criteria not met, n=30 Withdrew consent, n=22 Lost to followup, n=5 Protocol deviation, n=1 *Patients who discontinued therapy but had experienced both regimens and completed the Dosing Regimen Questionnaire were included in the final results.
Fig. 2. Participant assessment and followup throughout the study.
D. Kendler et al. / Maturitas 48 (2004) 243–251 hypertension (114, 28%), osteoarthritis (46, 11%), hy- imen first preferring the once weekly regimen. There- percholesterolemia (36, 9%) and hypothyroidism (32, fore, no effect by sequence was seen (P = 1.000).
Of the 360 (91%) participants who expressed that All participants randomised received at least one one regimen is more convenient, 314 (87%) consid- dose of study medication. A total of 390 (97%) par- ered the once weekly regimen to be more convenient ticipants took all 4 of their weekly tablets and 344 (P < 0.001). For the question asking which regimen (86%) participants took all 28 of their daily tablets.
they would be more willing to take for a long period Three hundred and ninety-six took at least one dose of time, 369 (93%) indicated a choice between reg- from each regimen and all of these completed the ques- imens. Of those, 311 (84%) indicated that the once tionnaire. Three hundred and eighty-four participants weekly regimen is the one they would be more willing (95%) completed the study. The most common reason to take long term (P < 0.001).
for early discontinuation was a clinical adverse expe-rience (15, 4%) There was no apparent effect of any of the sub- groups studied on preference for dosing regimen Of the 396 participants who completed the ques- (Also, responses were similar regardless of tionnaire and experienced both regimens, 364 (92%) expressed a preference for one of the two treatmentregimens. Of these, 305 (84%) preferred the once weekly regimen and 59 (16%) preferred the once dailytreatment regimen The preference for the Of the 406 randomised participants who took at once weekly regimen was statistically significant (P < least one dose of study medication, 403 participants 0.001). The preference for the once weekly regimen took at least one weekly dose and 399 took at least one was similar in the two sequence groups, with 149 daily dose. Of these participants, 99 (25%) had an ad- (84%) of those who took the once weekly regimen verse experience during the weekly regimen and 110 first expressing a preference for once weekly, and 156 (28%) during the daily regimen. The most frequently (84%) of the participants who took the once daily reg- occurring adverse experiences were in the categories Fig. 3. Participant responses to questionnaire on parameters of preference, convenience and willingness to take long term after experiencingboth alendronate once weekly and once daily regimens. P < 0.001 for each parameter.
D. Kendler et al. / Maturitas 48 (2004) 243–251 A similar study of alendronate conducted in a US population demonstrated similar results to our inter- national study indicating a preference for once weekly dosing regardless of country of residence.
These two studies are the first to investigate patientpreference for weekly dosing as compared to daily dosing for a chronic condition. Other oral medica- tions are dosed weekly, including chloroquine and More than 75% of time with a concomitant medication arthritis cabergoline for prolactinoma anti- fungals such as fluconazole and fluoxetine for continuation therapy for depression Whether patients would also prefer weekly therapy to daily for these other medications is not known.
Information about patient preference for dosing reg- imens also can be obtained from anecdotal experiences and from surveys of a target patient population. How-ever, each of these approaches has drawbacks. There Number of concomitant chronic medications are few reports of preference in dosing regimen after allowing volunteers to experience different regimens, and none that have addressed this issue for weekly dos- Preference for once weekly dosing with alendronate was sim- ilar regardless of subgroup tested, including country of residence ing for osteoporosis. This trial was designed to mimic clinical practice as much as possible in the clinical trialsetting. The randomised, open-label, crossover design,with 4 weeks allotted for each regimen, was chosen to of body as a whole (10% and 8% for once weekly and allow the participants an adequate amount of time on once daily respectively) and digestive system (7% and each regimen to assess their preference. Four weeks 10%, respectively). The occurrence of adverse expe- was chosen as an adequate amount of time to assess riences (among participants who received at least one how well the regimen is received by the participant in dose of both regimens) was not statistically different relation to her usual daily and weekly activities. The between the two treatment regimens (P = 0.158).
4-week treatment period for each regimen was cho-sen to be short enough to minimize recall bias. Thestrength of the results of this study was confirmed by 4. Discussion
the lack of sequence effect on the results, suggestingthat recall bias did not occur in this trial.
In this study, we investigated the attitudes among Patient preference for a therapy may also be deter- postmenopausal women from 19 countries toward two mined by factors other than dosing regimen. Efficacy, alendronate dosing regimens, once weekly or once safety, and tolerability (whether perceived or real) will daily dosing, for treatment of osteoporosis. For the ma- also be important factors in preference for one therapy jority of the women, the once weekly regimen was the or regimen over others. In this study, attempts were one they preferred, found more convenient, and would made to design the trial to focus solely on the treat- be more willing to take for a long period of time (84, ment regimen itself. We attempted to minimise any 87, and 84%, respectively). Understanding patient at- perceptions of differential effects on efficacy by stating titudes toward various dosing regimens is an impor- to the participants, consistent with controlled clinical tant aspect of understanding which regimens are likely trial data that the once weekly and the once daily to enhance compliance to therapy, especially for dis- regimens had similar efficacy. Also, no efficacy param- orders such as osteoporosis which require long-term eters were tested during the study. No such statements were made about tolerability and therefore perceived D. Kendler et al. / Maturitas 48 (2004) 243–251 tolerability, at least for some participants, may have nant women led to higher compliance than did daily been a factor that influenced their preference for one regimen over the other. Patient preference may also be 100% compliance with the once weekly regimen than influenced by the perceptions of the investigators and with the daily regimen (97% versus 86%). Effective- study site personnel. We believe this potential bias is ness in reducing fractures in osteoporotic patients in- minimal in this study because the study was performed volves not only administration of an effective therapy prior to the availability of the once weekly alendronate but also administration of a therapy that the patient is regimen in the marketplace, because physicians had willing to take. Whether better long term compliance minimal prior experience with once weekly oral reg- with treatment for osteoporosis can be achieved with imens for chronic conditions, and because of the ini- regimens designed to enhance patient convenience and tial skepticism expressed by many physicians about preference deserves additional investigation.
patients’ willingness to take a weekly rather than the In determining the best therapy for a particular pa- tient, efficacy and tolerability are important considera- To allow for adequate absorption, very specific dos- tions. In addition, ease of use and dosing convenience ing instructions are recommended for the bisphospho- are important features to consider to encourage long nates, including alendronate. These instructions may term compliance to therapy for chronic conditions be restrictive for some, especially for daily adminis- such as osteoporosis. This study demonstrated that, tration. The need to follow these strict dosing instruc- compared to once daily dosing, the once weekly dos- tions only once a week may have been a substantial ing regimen with alendronate was preferred, was more factor in the preference for weekly over daily dosing.
convenient, and was the regimen patients were more Whether similar preference for weekly over daily dos- willing to take for a long period of time. For chronic ing would be seen for a therapy with fewer dosing therapy such as is required for osteoporosis, it is im- restrictions cannot be determined from this study.
portant for physicians to consider patient preferences The participants’ assessment of the dosing regimens in order to help optimise compliance to therapy.
in this study was limited to the three questions in theDosing Regimen Questionnaire. Qualitative informa-tion about reason for the preferred regimen was not Acknowledgements
collected. In the subgroup analysis we investigated We would like to thank Larry Radican and Julie factors that may be associated with a preference for Chandler for contributing their expertise to the de- one regimen over the other, including age, country of velopment of the Dosing Regimen Questionnaire. We residence, and complexity of coexisting medical care would like to acknowledge both the women partici- as measured by presence of concomitant medication pants, without whom this investigation would not have use, number of active medical conditions (other than been possible, as well as the contributions of the per- osteoporosis), and number of concomitant medica- sonnel at the study sites. Funding as well as study tions. In addition, we evaluated the preference in sub- medication, monitoring, and statistical support were groups with common active medical conditions. All of the subgroups investigated not only preferred theonce weekly regimen, but also had a similar prefer-ence for the once weekly regimen to that of the overall References
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