5 year long 1mg Finasteride Study
Long-term (5-year) multinational experience with finasteride 1 mg in the treatment of men with androgenetic alopecia
European Journal of Dermatology. Volume 12, Numéro 1, 38-49, January - February 2002, Thérapie
Summary
Auteur(s) : The Finasteride Male Pattern Hair Loss Study Group, Merck Research Laboratories, 126 East Lincoln Avenue, RY33-500, Rahway, NJ 07065, USA..
Androgenetic alopecia (male pattern hair loss, MPHL) occurs in men with an inherited sensitivity to the effects of androgens on scalp hair [1, 2]. The disorder is characterized by loss of visible hair over areas of the scalp due to progressive miniaturization of hair follicles [3-5]. MPHL does not occur in men with genetic deficiency of the Type 2 5alpha-reductase (5alphaR) enzyme, which converts testosterone (T) to dihydrotestosterone (DHT), implicating DHT in the pathogenesis of this condition [6]. Of the two 5alphaR isoenzymes in man [7-9], Type 1 predominates in sebaceous glands of the skin, including scalp [10, 11], while Type 2 is present in hair follicles [12], as well as the prostate [11].
Finasteride, a Type 2-selective 5alphaR inhibitor, lowers serum [13], prostate [14] and scalp [15, 16] DHT levels after oral administration. Developed for the treatment of men with benign prostatic hyperplasia (BPH) at a dose of 5 mg/day, finasteride has a well-established, excellent safety profile [13, 17]. Subsequent studies in men with MPHL showed that finasteride had utility in this disorder as well [18-20], and confirmed 1 mg/day as the optimal dose for treatment of this condition. Three randomized, placebo-controlled, multicenter Phase III trials in men with MPHL demonstrated that treatment with finasteride 1 mg/day produced significant improvements in scalp hair growth and led to increased patient satisfaction with the appearance of their scalp hair [19-21]. In contrast to its beneficial effects in men with MPHL, finasteride was shown to lack efficacy in postmenopausal women with androgenetic alopecia in a 1-year, randomized, placebo-controlled trial [22]. As a Type 2 5alphaR inhibitor, finasteride use is contraindicated in women who are or may potentially be pregnant because of the potential risk of under-virilization of a male fetus.
Because finasteride is used chronically for the treatment of men with MPHL, it was important to evaluate the long-term safety and efficacy of the drug in these men. The present analysis investigated the combined safety and efficacy data over five years from the two replicate, Phase III clinical trials in men with predominantly vertex MPHL. Both trials involved an initial 1-year placebo-controlled study period, followed by four consecutive, 1-year placebo-controlled extension study periods.
Materials and methods
Study population
Full methodological details of the two Phase III studies included in this analysis have been reported previously [19]. Men aged 18 to 41 years, with mild to moderately severe vertex MPHL according to a modified Norwood/Hamilton classification scale (II vertex, III vertex, IV or V) [23, 24], were enrolled. Principal exclusion criteria included significant abnormalities on screening physical examination or laboratory evaluation, surgical correction of scalp hair loss, topical minoxidil use within one-year, use of drugs with androgenic or antiandrogenic properties, use of finasteride or other 5alphaR inhibitors, or alopecia due to other causes. Men were instructed not to alter their hairstyle or dye their hair during the studies.
Study protocols
Two initial, 1-year, randomized, double-blind, placebo-controlled studies were initiated, and both were continued as four consecutive, 1-year, double-blind, placebo-controlled extension studies. The objectives of the controlled extension studies were to determine the effect of long-term (up to five years) treatment with finasteride 1 mg/day, the effect of withdrawing treatment after one year, the effect of delaying treatment by one year, and the progression of MPHL in men not receiving active treatment. Investigators participated at 33 sites in the US and 27 sites in 15 countries outside the US. Institutional review board approval and written informed consent were obtained each year prior to entering subjects into each study.
1-year initial studies
Following a screening procedure, study subjects entered a 2-week, single-blind, placebo run-in period. All men received study shampoo (Neutrogena T/Gel®) for standardization of shampoo used and for prophylaxis of seborrheic dermatitis, which might affect scalp hair growth [25]. Subjects (N = 1,553) were then randomized to finasteride 1 mg/day or placebo (1:1) for one year (Figs. 1 and 2).
Men visited the clinic every 3 months, where they completed a hair growth questionnaire and investigators completed assessments of scalp hair growth. Every 6 months, photographs of scalp hair were taken for hair counts and for the expert panel assessment of hair growth. Reports of adverse events were collected throughout the studies.
1-year extension studies
Men completing the initial 1-year, placebo-controlled studies were eligible to enroll in four consecutive, 1-year, placebo-controlled extension studies. In the first extension studies, men (N = 1,215) were randomly assigned (as determined at initial randomization) to treatment with either finasteride 1 mg or placebo (9:1), such that men were randomized to one of four treatment groups that allocated treatment to them during both the initial 1-year studies (year 1) and the first 1-year extension studies (year 2): finasteride => finasteride, finasteride => Pbo, Pbo => finasteride, or Pbo => Pbo (Figs. 1 and 2). In the three subsequent, 1-year extension studies (years 3 to 5), men continued on the same treatment they had received during the first extension studies (year 2) except for men in the finasteride => Pbo crossover group; those men were switched back to finasteride (finasteride => Pbo => finasteride) during the second extension studies (year 3) and remained on that therapy throughout the subsequent extension studies (years 4 and 5).
The procedures for the first 1-year extension studies (year 2) were similar to those for the initial 1-year studies, except that hair counts were obtained only once, at month 24. In the remaining three 1-year extension studies (years 3 to 5), all efficacy evaluations were performed once yearly.
Evaluation procedures
Efficacy measurements
Four predefined efficacy endpoints provided a comprehensive assessment of changes in scalp hair from baseline: (1) hair counts, obtained from color macrophotographs of a 1-inch diameter circular area (5.1 cm2) of clipped hair (length 1 mm), centered at the anterior leading edge of the vertex thinning area; (2) patient self-assessment of scalp hair, using a validated, self-administered hair growth questionnaire; (3) investigator assessment of scalp hair growth, using a standardized 7-point rating scale; and (4) independent assessment of standardized clinical global photographs of the vertex scalp by a panel of three dermatologists (E. Olsen, R. Savin, D. Whiting) who were blinded to treatment and experienced in photographic assessments of hair growth, using the standardized 7-point rating scale.
Safety measurements
Safety measurements included clinical and laboratory evaluations, and adverse experience reports.
Laboratory evaluation
Hematology and serum chemistries were performed at baseline and every 6 months up to month 24, then yearly thereafter. Hormone measurements were performed at baseline and every 6 months up to month 24, and then at the end of the last extension studies (month 60). Hematology was analyzed in the local laboratory at each study site while serum chemistries, including prostate-specific antigen (PSA), and serum hormones, including testosterone, DHT, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), were assayed in central laboratories (Medical Research Laboratories, Highland Heights, KY and Endocrine Sciences, Calabasas Hills, CA, respectively).
Statistical analysis
A data analysis plan pre-specified all primary and secondary hypotheses, including combining data from the two initial, 1-year, phase III studies to improve precision of the estimates of the treatment effect, as well as from each of the 1-year controlled extensions due to the small size of the placebo groups in those studies.
Hair counts were assessed by the difference between the count at each time point versus the baseline count, and mean hair count values for each treatment group were determined using SASâ„¢ Least Squares Means. Each of the seven questions in the patient self-assessment of hair growth was assessed separately, and the responses to each question at each time point were taken as assessments of changes from baseline. The investigator assessments of hair growth and the expert panel assessments of global photographs were assessed by comparison of mean rating scores for each treatment group at each time point, based on the 7-point rating scale (minimum value = - 3.0 [greatly decreased]; maximum value = 3.0 [greatly increased]). Hypothesis testing for hair counts, individual patient self-assessment questions, and investigator and global photographic assessments was performed using analysis of variance (ANOVA). The ANOVA model included terms for treatment and protocol. For analysis of serum testosterone and DHT, the Wilcoxon Rank Sum test and the associated Hodges-Lehmann estimator were used to determine the median differences and the associated confidence intervals and p-values.
The primary efficacy analysis population for this report was the intention-to-treat population, which included all subjects with at least one day of randomized therapy and with both baseline and at least one post-baseline efficacy assessment. For all efficacy analyses, missing data were estimated by carrying data forward from the previous visit. However, no data were carried forward from the baseline evaluation, or between the initial 1-year study and the first 1-year extension study, or between the extension studies. A secondary population for analysis of efficacy included only the data from the cohort of men who completed the 5-year study.
Safety analyses were based on all subjects with at least one day of randomized therapy. The safety analyses focused on the biochemical parameters, using ANOVA, and on adverse experience reports.
Results
Patient accounting and baseline characteristics
Patient accounting is summarized in Figure 1. A summary of baseline characteristics for men who entered the first extension study (year 2) is presented by treatment group in Table I. Demographics and baseline characteristics were comparable among the four treatment groups.
Hair counts
In the group that received finasteride for up to five years (finasteride => finasteride), there were significant increases in hair counts over five years (p < 0.001 versus baseline for all time points), which reached a maximal increase at month 12 (mean increase [95% CI] from baseline at month 12 = 91 [84, 98] hairs in the target area), declined somewhat thereafter but remained above baseline throughout, with a mean increase of 38 [21, 56] hairs at month 60 (Fig. 3). In contrast, in the group that received placebo for up to five years (Pbo => Pbo), there was a progressive decline in hair counts over five years (p < 0.001 versus baseline for months 24-60), culminating in a mean decrease from baseline of - 239 [- 304, - 173] hairs at month 60 (Fig. 3). Taken together, the hair counts measured in the finasteride => finasteride and Pbo => Pbo groups over five years resulted in a progressive increase in the difference between these two groups over time (mean differences [95% CI] in the changes from baseline): 107 [85, 130] hairs at month 12, 138 [107, 170] hairs at month 24, 146 [106, 185] hairs at month 36, 216 [161, 271] hairs at month 48, and 277 [209, 345] hairs at month 60 (p < 0.001 for all between-group comparisons). Similar results were observed based on an analysis of hair count data for the cohort of men who completed the 5-year study (Fig. 4). Sixty-five per cent (143/219) of finasteride-treated men (finasteride => finasteride) had increased in hair counts at five years, compared to none (0/15) of the placebo-treated (Pbo => Pbo) men. Conversely, hair loss by hair count was demonstrated in all men in the Pbo => Pbo group (15/15) at five years, in contrast to 35% of men (76/219) in the finasteride => finasteride group. Furthermore, the decrease in hair count for the minority of men who lost hair while receiving finasteride for five years was less (- 84 [- 101, - 67] hairs from baseline) than the decrease observed in men receiving placebo over the same time period (- 239 [- 304, - 173] hairs from baseline).
For the group crossed over from placebo to finasteride after one year (Pbo => finasteride), there was a decrease in hair count during the year of placebo treatment (mean change from baseline = - 20 [- 27, - 12] hairs at month 12; p < 0.001). This initial loss of hair on placebo was followed by significant increases in hair count during treatment with finasteride through month 60 (p < 0.001 versus month 12 for months 24-48; p < 0.050 versus month 12 for month 60), with maximal improvement observed at month 24 (12 months on finasteride) (Fig. 3). Increases in hair count during finasteride treatment in this group were generally sustained over time, although the increases compared to baseline were consistently less than those observed in the finasteride => finasteride group at comparable time points, with the difference being similar in magnitude to the amount of hair loss sustained during the year of placebo treatment. For the group that received finasteride for one year, was crossed over to placebo for one year, and was then switched back to finasteride (finasteride => Pbo => finasteride), the beneficial effect on hair count seen during the first year of finasteride treatment was reversed after one year of placebo treatment. Benefit was restored after resumption of therapy with finasteride through month 60 (Fig. 3).
Patient self-assessment
For each of the seven questions in the patient self-assessment questionnaire, treatment with finasteride (finasteride => finasteride) was superior to treatment with placebo (Pbo => Pbo) at each time point (p < 0.001 for all between-group comparisons). The finasteride => finasteride group demonstrated significant (p < 0.001) improvement from baseline at each time point for each question, with the exception that there was no significant difference from baseline at the month 12 time point for Question 5a (assessment of satisfaction with appearance of the frontal hairline), whereas the Pbo => Pbo group generally demonstrated deterioration from baseline over time. For each of the seven questions, a greater proportion of finasteride- versus placebo-treated subjects reported an improvement from baseline, with the difference between groups increasing over time (Fig. 5 and Table II).
In the Pbo => finasteride group, there was generally sustained improvement following one year of placebo treatment for each question during the period of finasteride treatment (p < 0.001 versus month 12 for months 24-60), although, as with hair counts, this improvement was less than that seen in the finasteride => finasteride group at comparable time points. For the finasteride => Pbo => finasteride group, partial to complete reversibility of the beneficial effect of finasteride was observed for six of the seven questions after one year of placebo treatment, with the beneficial effect being partially restored following resumption of finasteride treatment.
Investigator assessment
Based on the investigator assessment, treatment with finasteride (finasteride => finasteride) was superior to treatment with placebo (Pbo =>Pbo) at each time point (p < 0.001, all comparisons) (Fig. 6). By month 60, the investigators rated 77% of subjects in the finasteride => finasteride group as having improved compared to 15% in the Pbo => Pbo group (Table II). As anticipated, the Pbo => finasteride group showed improvement during the period of finasteride therapy through month 60 (p < 0.001 versus. month 12 for months 24-60), although as with hair counts and patient self-assessment the magnitude of this improvement was less than that seen in the finasteride => finasteride group at comparable time points (Fig. 6). In contrast to the other endpoints, the investigator assessment did not demonstrate worsening from baseline for the Pbo => Pbo group until month 36, after which time point further deterioration through month 60 was observed (Fig. 6). For the finasteride => Pbo => finasteride group, there was initial improvement during the first year of finasteride treatment, followed by a plateau during the year of placebo treatment and then restoration of improvement following resumption of finasteride treatment.
Global photographic assessment
Based on the global photographic assessment, treatment with finasteride (finasteride => finasteride) was superior to treatment with placebo (Pbo => Pbo) at each time point (p < 0.001, all comparisons) (Fig. 7). At month 60, 48% of finasteride-treated subjects were rated as slightly, moderately, or greatly improved compared to 6% of placebo-treated subjects. Viewed in the context of maintaining visible hair from baseline, 90% of subjects treated with finasteride demonstrated no further visible hair loss by this assessment, compared to 25% of patients on placebo. Conversely, 75% of men treated with placebo demonstrated further visible hair loss at five years, compared to 10% of men on finasteride (Table II and Fig. 8). For the finasteride => finasteride group, maximal improvement by global photographic assessment was observed at month 24, declined somewhat thereafter, but remained above baseline throughout (p < 0.001 versus baseline for all time points) (Fig. 7). In contrast, the Pbo => Pbo group demonstrated progressive worsening by global photographic assessment through month 60 (p < 0.010 versus baseline for month 24; p < 0.001 versus baseline for months 36-60) (Fig. 7). The Pbo => finasteride group also demonstrated sustained improvement in mean score during the period of finasteride treatment from month 12 to month 60 (p < 0.001 versus month 12 for months 24-60), although, as with the three other efficacy measures, the magnitude of improvement was less than that seen in the finasteride => finasteride group for comparable time points (Fig. 7). For the finasteride => Pbo => finasteride group, the beneficial effect of finasteride was reversed after 12 months of placebo treatment (p < 0.001, month 24 versus month 12), with the beneficial effect partially restored upon resumption of finasteride therapy (Fig. 7).
Global photographs of representative subjects from the Pbo => Pbo and finasteride => finasteride groups who were rated by the expert panel as having decreased or increased hair growth from baseline are shown in Figure 9.
Serum hormones and PSA
As anticipated, treatment with finasteride produced a marked and sustained reduction in serum DHT. For the cohort of men in the finasteride => finasteride and Pbo => Pbo groups with month 60 data, the median baseline serum DHT levels were identical (44.0 ng/dL; normal range = 30-85 ng/dl) and median serum testosterone levels were similar (510 and 496 ng/dl, respectively; normal range = 350-1,030 ng/dl). At month 60, treatment with finasteride led to a median difference between the treatment groups of - 55% [- 68.6, - 45.3] (p < 0.001) for serum DHT and 7.0% [- 6.8, 21.6] (p = 0.315) for serum testosterone. Finasteride treatment had no significant effect on serum LH or FSH compared to placebo, while serum PSA was slightly decreased from a mean baseline of 0.7 ng/ml [normal range < 4.0 ng/mL] to 0.5 ng/ml at month 60 [p < 0.010 versus baseline], leading to a mean difference [95% CI] between the finasteride => finasteride and Pbo => Pbo groups of - 0.3 ng/ml [- 0.5, -0.2] at month 60 (p < 0.001).
Adverse events
Clinical adverse experiences that were considered by the investigator to be possibly, probably or definitely drug-related and that occurred in at least 1% of men are summarized in Table III. As reported previously, in the first year a slightly higher proportion of finasteride than placebo subjects reported drug-related adverse experiences related to sexual function (4.4% versus 2.2%, p = 0.030) (Table III), and only 11 men (1.4%) treated with finasteride and 8 (1.0%) treated with placebo discontinued the studies due to these side effects. These side effects resolved after discontinuation and also resolved in most men who reported them but remained on therapy with finasteride. The adverse experience profile for men continuing in the extension studies was similar to that of the initial studies, and only 7 (1.3%) of the 547 men in the finasteride => finasteride group who continued in the extension studies were withdrawn due to drug-related sexual adverse experiences over the ensuing four years (Table III).
Discussion
The data from these two replicate Phase III studies and their long-term extensions represent the longest reported controlled observations in men with MPHL. The combined analysis demonstrated that long-term treatment with finasteride led to significant and durable improvements, compared to both baseline and placebo, in scalp hair in men with MPHL. Hair counts increased over the first year of treatment with finasteride, with improvement above baseline maintained over five years. In contrast, the placebo group progressively lost hair over five years, confirming the natural progression of hair loss in this disorder due to the continued miniaturization of scalp hair. Thus, the treatment effect of finasteride on hair count relative to placebo increased progressively over time, leading to a net improvement for finasteride-treated men of 277 hairs compared to placebo at five years. Most (65%) finasteride-treated men had increases in hair count at five years, compared to none of the placebo-treated men, but even for those finasteride-treated men with less hair by hair count at five years, the magnitude of loss was less than that observed in the placebo group. These data support that the progression of hair loss observed in placebo-treated men was significantly reduced by treatment with finasteride.
Based on the predefined endpoints utilizing photographic methods (hair counts and global photographic assessment), peak efficacy was observed at one to two years of treatment with finasteride. This observation of an apparent peaking effect is likely due, in part, to the previously-reported beneficial effects of finasteride on the hair growth cycle based on a phototrichogram study [26]. In that study, initiation of finasteride treatment was shown to increase the number of anagen-phase hairs and to increase the anagen to telogen ratio, consistent with normalization of the growth cycles of previously miniaturized hairs due to the release of hair follicles from the inhibitory effects of DHT [26]. Consistent with these results, finasteride treatment was also shown to increase the growth rate and/or thickness of hairs, based on analysis of serial hair weight measurements [27]. Because these beneficial changes in the hair growth cycle are dependent on when therapy with finasteride is initiated and occur rapidly, the affected hairs are driven to cycle in a synchronous manner. If these hairs have somewhat similar anagen phase durations, they would enter telogen phase as the anagen (and catagen) phase ended, followed by subsequent shedding, in a partially synchronized fashion. This would be expected to produce a gradual decline from peak hair count after a period of time equal to the average anagen phase duration. Eventually, as subsequent growth cycles recurred, these hairs would be expected to become increasingly independent, thereby losing their synchronous character as their growth cycles further normalized over time, leading to a sustained increase in hair count at a plateau above baseline, as suggested by the 5-year data presented here.
Patient self-assessment of hair growth provides a mechanism for each subject to judge the benefits of treatment under controlled and blinded conditions. This questionnaire asks specific questions about the patient's hair growth or loss and his degree of satisfaction with the appearance of his hair compared to study start. While a placebo effect was observed with this instrument, as is typical of patient questionnaire data, results consistently demonstrated that men treated with finasteride had a more positive self-assessment of their hair growth and satisfaction with their appearance than men treated with placebo, with the majority of finasteride-treated men reporting satisfaction with the overall appearance of their scalp hair at 5 years. Consistent with the findings of another study in which finasteride was evaluated in men with predominantly frontal MPHL [20], patients' satisfaction with the appearance of their frontal hairline was improved by treatment with finasteride in the present studies.
The investigators' assessments are based on observations of subjects seen in the clinic and provide a clinically relevant assessment of the patient's hair growth or loss since study start. These assessments demonstrated a sustained benefit of finasteride treatment over five years. Although there was no change in the improvements reported for finasteride-treated subjects between month 24 and month 60, there was significant deterioration reported for placebo-treated subjects during the same time period. Thus, the treatment effect as assessed by the investigators increased between months 24 and 60, indicating further separation between the treatment groups over time. As with the patient self-assessment, the investigator assessment had a greater placebo effect than the more objective endpoints of hair count and global photographic assessment. Such an effect is not unusual in double-blind, placebo-controlled studies, and is often due to a general expectation bias on the part of the patient's treating physician. Despite this apparent placebo effect, the beneficial effects of finasteride were demonstrated by the clinical assessments made by the investigators in these studies. In contrast to the investigator assessment, the blinded comparison of paired pre- and post-treatment global photographs by the expert panel, which also assessed change from baseline, demonstrated minimal, if any, placebo effect. Based on this assessment, finasteride treatment led to maintenance of improvement above baseline in scalp hair growth and scalp coverage over five years, while placebo subjects progressively worsened. Treatment with finasteride for five years led to sustained protection against further visible hair loss in nearly all (90%) subjects, while further visible hair loss was evident in most (75%) subjects treated with placebo over the same time period.
While the number of patients remaining in the study declined over time and the size of the placebo group was limited in the extension studies, the results of analyses that included either all available patients at each time point or only the cohort of patients with data at month 60 were consistent and supported a sustained benefit in hair growth for men receiving finasteride 1 mg compared with placebo. Additionally, examination of data from placebo-treated men in all cohorts demonstrated the continued loss of scalp hair that occurs in untreated men with MPHL. Thus, regardless of the cohort examined, the long-term data from these studies consistently demonstrated a beneficial effect of finasteride compared with placebo for men with MPHL. Moreover, this beneficial effect increased over time due to the progressive increase in the net treatment effect of finasteride compared with placebo.
The safety data from the five years of controlled observations in the current studies provide reassurance that long-term use of finasteride 1 mg in men with MPHL is not associated with an increase in the incidence of adverse experiences or any new safety concerns. As in all clinical studies with finasteride, a marked and persistent suppression of serum DHT levels was observed in finasteride-treated subjects, but this was not associated with significant changes in serum gonadotropins (LH and FSH). These data are consistent with previous data on the lack of effect of finasteride on the hypothalamic pituitary-gonadal axis in young men [21, 28]. As expected, based on the previously reported experience with finasteride, a few men in the current studies experienced reversible impairment of sexual function. However, less than 2% of men receiving finasteride discontinued treatment for this reason, compared with 1% of men in the placebo group, with resolution occurring after discontinuation of drug. No other significant adverse effects of finasteride were observed in the patient population evaluated in the current studies. This excellent safety profile of long-term use of finasteride is consistent with the experience with the drug at five times the dose used in the present studies that has been well-documented in large clinical trials and post-marketing surveillance over nine years in men with BPH [13, 17, 29]. In light of the well known inhibitory effect of finasteride on growth of the prostate gland, the modest reduction in serum PSA observed in finasteride-treated subjects over five years was not unexpected. For men in whom serum PSA is used as part of a screening evaluation for prostate cancer, guidelines have been published for interpretation of PSA levels in men receiving finasteride treatment [29-31].
In summary, treatment with finasteride 1 mg/day over five years increased scalp hair as determined by scalp hair counts, patient self-assessment, investigator assessment, and global photographic assessment, when compared with placebo. In contrast, data from the placebo group confirmed that without treatment progressive reductions in hair count and continued loss of visible hair occurs. Long-term treatment with finasteride 1 mg/day was generally well tolerated. The results of these studies demonstrate that chronic therapy with finasteride leads to durable improvements in hair growth in men with MPHL and slows the further progression of hair loss that occurs without treatment.
* The Finasteride Male Pattern Hair Loss Study Group includes (in alphabetical order, by country):
AUSTRIA
D. Kopera, Graz
J. Schmidt, Vienna
BELGIUM
J.-M. Lachapelle, Jumet
D. Van Neste, Tournai
BRAZIL
D. Steiner, Sao Paulo
CANADA
P. Cotterill, Toronto
D. Gratton, Montreal
P. Reardon, Halifax
J. Shapiro, Vancouver
W. Unger, Toronto
FRANCE
P. Reygagne, Paris
P. Saiag, Billancourt
GERMANY
H. Wolff, Munich
ISRAEL
S. Brenner, Tel-Aviv
MEXICO
F. Jurado Santa-Cruz, Mexico City
NETHERLANDS
I. Boersma, Zwijndrecht
E. Prens, Vlissingen
NEW ZEALAND
N. Birchall, Auckland
NORWAY
C. Mork, Oslo
SOUTH AFRICA
J. Cilliers, Tygerberg
M. Sher, Johannesburg
G. Todd, Capetown
SPAIN
E. Lopez-Bran, Madrid
P. Sanchez-Pedreno, El Palmar
SWITZERLAND
G. Burg, Zurich
T. Rufli, Basel
UK
W. Cunliffe, Leeds
S. MacDonald-Hull, Pontefract
A. McDonagh, Bradford
USA
W. Bergfeld, Cleveland, OH
D. Buntin, Hermitage, TN
R. DeVillez, San Antonio, TX
L. Drake, Boston, MA
V. Fiedler, Chicago, IL
D. Fivenson, Detroit, MI
T. Funicella, Austin, TX
C. Gencheff, Madison, WI
M. Hordinsky, Minneapolis, MN
S. Horwitz, Miami Beach, FL
J. Imperato-McGinley, New York, NY
I. Katz, Fridley, MN
A. Kelly, Los Angeles, CA
R. Langley, Boston, MA
N. Lowe, Santa Monica, CA
A. Lucky, Cincinnati, OH
C. McCall, Atlanta, GA
E. Olsen, Durham, NC
G. Peck, Washington, DC
V. Price, San Francisco, CA
R. Rietschel, New Orleans, LA
J. Roberts, Portland, OR
N. Sadick, New York, NY
S. Savage, Denver, CO
R. Savin, New Haven, CT
J. Shupack, New York, NY
D. Stewart, Clinton Township, MI
D. Stough, Hot Springs, AR
J. Swinehart, Denver, CO
L. Swinyer, Salt Lake City, UT
K. Washenik, New York, NY
G. Weinstein, Irvine, CA
D. Weiss, Fairlawn, NJ
J. Weiss, Snellville, GA
D. Whiting, Dallas, TX
E. Whitmore, Baltimore, MD
and
B. Binkowitz, W. He, M. Sanchez
Dept. of Biostatistics
K. Kaufman, E. Round, P. Ruane
Dept. of Clinical Research
Merck Research Laboratories, Rahway, NJ
CONCLUSION
Acknowledgements
This study was supported by a grant from Merck & Co., Inc. The authors wish to acknowledge the technical assistance of Mr. Douglas Canfield, of Canfield Scientific, Inc., in the development of photographic procedures used in these clinical studies. The authors also wish to thank Dr. Alan Meehan, Merck & Co., Inc. for his assistance in preparing this paper for publication.
Article accepted on 15/11/01
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