Synopsis

Document Sample
Synopsis Powered By Docstoc
					Activelle Low Dose                                                        Date:                 12 January 2006     Novo Nordisk
Trial ID: ALD-1537                                                        Version:                           2.1
Integrated Clinical Trial Report                                          Status:                          Final
Report Synopsis                                                           Page:                           1 of 6


Synopsis
TITLE OF TRIAL
CHOICE: Clinical Study on Hormone Dose Optimisation in Climacteric Symptom Evaluation

A six month double-blind, randomised, parallel-group, placebo-controlled, multi-centre trial to investigate the
efficacy and safety of two ultra-low dose combinations with 0.5 mg estradiol and 0.1 mg or 0.25 mg
norethisterone acetate (Activelle Low Dose 0.1/Activelle Low Dose 0.25) for treatment of menopausal
symptoms
INVESTIGATORS
Seventy-seven Investigators participated in the trial.
TRIAL SITES
Seventy-seven centres participated: 2 in Austria, 8 in Belgium, 8 in Denmark, 5 in Finland, 3 in France, 9 in
Germany, 8 in Norway, 8 in Sweden, 4 in Switzerland and 22 in the United Kingdom.
PUBLICATIONS
Panay N, Ylikorkala O, Archer DF, Lang E, Gut R. Ultra low dose estradiol and norethisterone acetate:
Effective menopausal symptom relief. Abstract published in Climacteric Vol. 8, Suppl. 2, Oct. 2005, and
presented during 11th World Congress of the Menopause, Buenos Aires, October 2005.
Sturdee D, Archer DF, Lang E, Gut R. Ultra low dose estradiol and norethisterone acetate: Further reduction
in unwanted bleeding. Abstract published in Climacteric Vol. 8, Suppl. 2, Oct. 2005, and presented during
11th World Congress of the Menopause, Buenos Aires, October 2005.
Von Schoultz B, Lundström E, Bygdeson M, Svane G, Azavedo E, Lang E, Gut R. Ultra low dose estradiol
and norethisterone acetate: Is a neutral effect on the breast possible? Abstract published in Climacteric Vol. 8,
Suppl. 2, Oct. 2005, and presented during 11th World Congress of the Menopause, Buenos Aires, October
2005.
Samsioe G, Schönberg L, Lang E, Gut R. Ultra low dose estradiol and norethisterone acetate: Optimising
tolerability and safety? Abstract published in Climacteric Vol. 8, Suppl. 2, Oct. 2005, and presented during
11th World Congress of the Menopause, Buenos Aires, October 2005.
TRIAL PERIOD                                                            DEVELOPMENT PHASE
19 May 2004 - 04 May 2005                                               Phase 1
OBJECTIVES
Primary Objective:
• To assess the change in the mean number of moderate to severe hot flushes per week.
Secondary Objectives:
• To assess the influence of ALD 0.1 and ALD 0.25 on Hot Flush Weekly Weighted Score, percentage of
    responders to treatment, bleeding pattern, Greene Climacteric Scale, the occurrence and severity of
    urogenital symptoms, Maturation Value and vaginal pH.
METHODOLOGY
The trial was a double-blind, randomised, multi-centre, multi-national, placebo-controlled, parallel-group trial
to show the efficacy and safety of daily treatment with Activelle Low Dose 0.1 (ALD 0.1) and Activelle Low
Dose 0.25 (ALD 0.25) compared with placebo. The trial comprised a 2-3 week screening period, to assess
baseline menopausal symptoms, followed by 24 weeks of treatment with ALD 0.1, ALD 0.25 or placebo.
NUMBER OF SUBJECTS PLANNED AND ANALYSED
Planned: A total of 700 subjects were to be screened with 6 -10 subjects randomised to each trial product per
site. A total of 498 subjects were then to be randomised to receive trial medication (166 planned to receive
ALD 0.1, 166 ALD 0.25 and 166 placebo).
Analysed: 793 subjects were screened and 577 were randomised to receive trial medication (194 received
ALD 0.1, 182 received ALD 0.25 and 201 received placebo).
Activelle Low Dose                                                     Date:                 12 January 2006    Novo Nordisk
Trial ID: ALD-1537                                                     Version:                           2.1
Integrated Clinical Trial Report                                       Status:                          Final
Report Synopsis                                                        Page:                           2 of 6

Subject recruitment and disposition is summarised below:
                                    ALD 0.25           ALD 0.1             Placebo               All
                                       n (%)             n (%)              n (%)               n (%)
 Total Screened                                                                                  793
 Screening Failures                                                                              216
 Randomised                          182 (100)        194 (100)            201 (100)          577 (100)
 Received study medication            181 (99)        194 (100)            200 (>99)          575 (>99)
 ITT Population                       180 (99)        194 (100)             199 (99)           573 (99)
 Withdrew                              10 (5)            17 (9)             40 (20)            67 (12)
 Completed Trial                      171 (94)         177 (91)             160 (80)           508 (88)
 PP Population                        153 (84)         169 (87)             176 (88)           498 (86)

DIAGNOSIS AND MAIN CRITERIA FOR INCLUSION
The trial population comprised post-menopausal women aged 45 to 65 years, who had a minimum of 7
moderate to severe hot flushes per day or 50 moderate to severe hot flushes per week during the 2-week run-
in period.
TEST PRODUCT, DOSE AND MODE OF ADMINISTRATION, BATCH NUMBER
Trial subjects received one tablet per day of ALD 0.1 or ALD 0.25. ALD 0.l tablets contained 0.5 mg
estradiol and 0.1 mg norethisterone acetate (NETA). ALD 0.1 batch PBBA044 was used. ALD 0.25 tablets
contained 0.5 mg estradiol and 0.25 mg NETA. ALD 0.25 batch numbers used were PBBA045 and
PBBA095.
DURATION OF TREATMENT
Treatment continued for 24 weeks.
REFERENCE THERAPY, DOSE AND MODE OF ADMINISTRATION, BATCH NUMBER
Matched placebo tablets contained no active agent. Batch number NBBB008 was used for the trial.
CRITERIA FOR EVALUATION – EFFICACY
Hot flushes, Hot Flush Weekly Weighted Score, Greene Climacteric Scale, Urogenital symptoms, Maturation
Value and vaginal pH.
CRITERIA FOR EVALUATION – SAFETY
Bleeding profile, vital signs, physical examination, gynaecological examination, Papanicolaou cervical smear,
transvaginal ultrasound, mammographic changes, adverse events and laboratory assessments.
STATISTICAL METHODS
The primary endpoint for efficacy evaluation was the mean number of moderate to severe hot flushes per
week. The 8 week comparison was regarded as the primary time point, however the overall treatment effect
was assessed at 4 and 12 weeks. Additional treatment comparisons were also performed for weeks 1-4, 5-11
and week 24.
Primary Analysis
A closed testing procedure was adopted for the primary response variable. The primary efficacy analysis of
the number of moderate to severe hot flushes per week was performed on the changes from baseline by a
Kruskal-Wallis Test for the overall treatment comparison, and by a stratified Wilcoxon test, stratified by
country, for the paired treatment comparisons. Estimated median treatment differences and 95% two-sided
confidence intervals were constructed for the differences between pairs of treatments (ALD 0.1 vs. placebo,
ALD 0.25 vs. placebo, and ALD 0.1 vs. ALD 0.25). A Shapiro-Wilk test was performed to evaluate the
residuals for normality. The statistical analysis of the change in the frequency of moderate to severe hot
flushes from baseline to week 8 and the change in severity score from baseline to week 8 were summarised
and analysed as described for the primary endpoint as sensitivity analyses.
Activelle Low Dose                                                        Date:                  12 January 2006    Novo Nordisk
Trial ID: ALD-1537                                                        Version:                            2.1
Integrated Clinical Trial Report                                          Status:                           Final
Report Synopsis                                                           Page:                            3 of 6

Secondary Analyses
The number and percentage of subjects with at least a 90% improvement from baseline in their Hot Flush
Weekly Weighted Scores during each week of treatment was determined. Confidence intervals, based on the
binomial distribution, were determined using the percentage of subjects with at least a 90% improvement
from baseline in hot flush score at weeks 4, 8, 12 and 24, and statistical significance was assessed using the
Chi-squared test.
The Greene Climacteric Scale scores for each of the three dimensions were calculated separately and as a
total, by adding the scores for each symptom. The sexual interest and difficulty in sleeping questions were
analysed separately using the Kruskal-Wallis test to test the overall treatment effect, and the stratified
Wilcoxon rank sum test with the country as the stratification variable for paired comparisons.
A total urogenital symptom score was calculated as the sum of individual symptom scores divided by six for
sexually active subjects or by five for subjects where the dyspareunia question was ‘not applicable’. The
incidence of each of the urogenital symptoms was summarised but not analysed.
The Maturation Value was calculated by multiplying the percentage of each cell type by the following factors:
0.2 for parabasal, 0.6 for intermediate and 1.0 for superficial cells.
DEMOGRAPHY OF TRIAL POPULATION
The demographic characteristics of the trial population are summarised below:
                                                    ALD 0.25        ALD 0.1           Placebo        All
                                                    (N = 181)      (N = 194)         (N = 200)    (N = 575)
  Age (years)             Mean ± SD                 55.3 ± 4.4     55.2 ± 4.8     56.1 ± 4.7       55.5 ± 4.6
                          Range                     45.0 – 65.0    44.0 – 65.0    45.0 – 65.0      44.0 – 65.0
  Race n (%)              White                      172 (95)       182 (94)       191 (96)         545 (95)
                          Asian/Pacific Islander       1 (1)          2 (1)          1 (1)             4 (1)
                          Black                        2 (1)          0 (0)          0 (0)            2 (0)
                          Other                        0 (0)          1 (1)          1 (1)            2 (0)
                          Not available                6 (3)          9 (5)          7 (4)            22 (4)
  Body Weight             Mean ± SD                68.6 ± 11.1    66.6 ± 10.1    68.2 ± 10.3      67.8 ± 10.5
  (kg)                    Range                    46.8 – 101.5    45.0 – 94.1   46.2 – 105.0     45.0 – 105.0
                          Not recorded                   1              0              0                 1
                          Mean ± SD                 25.4 ± 3.5     25.0 ± 3.6     25.3 ± 3.6       25.3 ± 3.6
  BMI (kg/m2)
                          Range                     17.4 – 36.6    16.7 – 35.4    17.5 – 35.1      16.7 – 36.6
                          Not recorded                   1              0              0                 1
  Systolic Blood          Mean ± SD                127.7 ± 13.6   127.3 ± 14.9   128.6 ± 13.5     127.8 ± 14.0
  Pressure (mmHg)         Range                    80.0 – 159.0   95.0 – 162.0   80.0 – 158.0     80.0 – 162.0
                          Not recorded                   1              0              0                 1
  Diastolic Blood         Mean ± SD                 79.6 ± 8.4     78.2 ± 9.6     79.6 ± 8.7       79.1 ± 9.0
  Pressure (mmHg)         Range                     59.0 – 99.0    59.0 – 99.0   60.0 - 100.0     59.0 – 100.0
                          Not recorded                   1              0              0                 1
  Smokers n (%)                                       39 (22)        30 (15)        35 (18)         104 (18)
  Time Since Last         ≤ 1 year                    29 (17)        31 (19)        31 (17)          91 (18)
  Menses n (%)            > 1 – 2 years               20 (12)        20 (12)        19 (11)          59 (12)
                          > 2 – 5 years               40 (24)        46 (28)        39 (22)         125 (25)
                          > 5 – 10 years              51 (31)        39 (23)        50 (28)         140 (27)
                          >10 years                   26 (16)        30 (18)        39 (22)          95 (19)
Activelle Low Dose                                                        Date:                  12 January 2006    Novo Nordisk
Trial ID: ALD-1537                                                        Version:                            2.1
Integrated Clinical Trial Report                                          Status:                           Final
Report Synopsis                                                           Page:                            4 of 6

EFFICACY RESULTS
Primary Endpoint
• Both ALD 0.25 and ALD 0.1 resulted in a reduction in the number of moderate to severe hot flushes
    from week 3 until the end of the study. By week 8 of the trial (the primary time point) the mean numbers
    of moderate to severe hot flushes had fallen from 69.2 at baseline to 11.7 in the ALD 0.25 group, from
    70.9 at baseline to 17.4 in the ALD 0.1 group and from 70.0 at baseline to 38.2 in the placebo group.
    Statistically significant treatment differences were seen when comparing ALD 0.25 with placebo and
    ALD 0.1 with placebo from week 3 to week 24 (p < 0.001).
• Statistically significant (p < 0.001) treatment differences for the change in the number of moderate to
    severe hot flushes from baseline of -13.5 (CI -19.0, -8.4) for ALD 0.25 and -9.5 (CI -15.0, -4.5) for ALD
    0.1, compared with placebo, were seen at week 3. Treatment differences of -20.0 (CI -25.5, -14.6) for
    ALD 0.25 and -15.0 (CI -20.5, -9.6) for ALD 0.1, compared with placebo, were seen at week 4 and the
    changes at week 8 were -23.7 (CI -29.0; -18.2) for ALD 0.25 and -21.5 (CI -27.0; -16.5) for ALD 0.1,
    compared with placebo. These treatment differences also persisted for the duration of the trial with
    statistically significant differences of -20.5 (CI -26.5, -15.0) for ALD 0.25 and -19.5 (CI -25.5, -14.0) for
    ALD 0.1, compared with placebo, being seen at week 12.
• Sensitivity analysis showed that in the Activelle Low Dose treatment groups there was a greater
    reduction in hot flush severity score compared with placebo, with statistically treatment differences when
    comparing ALD 0.25 with placebo and ALD 0.1 with placebo from week 3 to week 24 (p = 0.001). The
    treatment differences at week 4 were –2.7 (CI –3.7; -1.8) for ALD 0.25 and –1.3 (CI -2.1; -0.7) for ALD
    0.1, compared with placebo; at week 8 they were -8.5 (CI -10.6; -6.1) for ALD 0.25 and -5.1 (CI -7.1; -
    3.4) for ALD 0.1, compared with placebo, and at week 12 they were -8.7 (CI -10.9; -6.6) for ALD 0.25
    and -6.1 (CI –8.6; -4.2) for ALD 0.1, compared with placebo.
• In general, there was no difference in efficacy between two ALD doses.
Secondary Endpoints
• All trial results were confirmed by all the secondary sensitivity analyses.
• In the Activelle Low Dose treatment groups there was a greater reduction in HFWWS compared with the
    placebo group, with statistically significant treatment differences when comparing ALD 0.25 with
    placebo and ALD 0.1 with placebo from week 4 to week 24 (p < 0.001). The treatment differences at
    week 8 were -58.8 (CI -73.5; -44.7) for ALD 0.25 and -55.0 (CI -69.0; -40.5) for ALD 0.1, compared
    with placebo.
• Analysis of the percentage of responders showed a statistically significant overall treatment effect at
    weeks 4, 8, 12 and 24 (all p = 0.001). Statistically significant treatment differences were seen when
    comparing ALD 0.25 with placebo and ALD 0.1 with placebo at all time points assessed (p = 0.001) and
    between ALD 0.25 and ALD 0.1 at week 8 (p = 0.003) and week 12 (p = 0.022). The proportion of
    subjects responding to the trial treatments (> 90% improvement in HFWWS) was 75% (CI 69; 81) for
    subjects in the ALD 0.25 group, 66 % (CI 59; 73) for subjects in the ALD 0.1 group and 23% (CI 17; 28)
    for subjects in the placebo group at week 24.
• In the Activelle Low Dose treatment groups there was a greater reduction in Greene Climacteric Scale
    total score compared with placebo, with statistically significant treatment differences when comparing
    ALD 0.25 with placebo and ALD 0.1 with placebo at all time points assessed (p = 0.001). The treatment
    differences at week 8 were -5.0 (CI -6.0; -3.0) for ALD 0.25 and -4.0 (CI -5.0; -3.0) for ALD 0.1,
    compared with placebo.
• Significant treatment differences in individual Greene Climacteric Scale parameters (psychological,
    vasomotor and difficulty sleeping scores) were also seen at all time points between ALD 0.25 and
    placebo and between ALD 0.1 and placebo. Statistically significant treatment differences in somatic
    scores were seen at weeks 4, 8 and 12 when comparing ALD 0.25 with placebo and at week 8 when
    comparing ALD 0.1 with placebo.
• Changes in urogenital symptom parameters did not show any notable differences between the treatment
    groups, with the exception of vaginal dryness where a higher proportion of subjects in the ALD groups
    reported no vaginal dryness at week 24 compared to the placebo group.
Activelle Low Dose                                                        Date:                 12 January 2006    Novo Nordisk
Trial ID: ALD-1537                                                        Version:                           2.1
Integrated Clinical Trial Report                                          Status:                          Final
Report Synopsis                                                           Page:                           5 of 6

•    The Maturation Values in the Activelle Low Dose treatment groups showed a comparable increase over
     the course of the trial; in contrast the Maturation Value in the placebo group decreased slightly.
     Statistically significant treatment differences (p = 0.001) were seen between ALD 0.25 and placebo at
     weeks 12 (6.8, CI 4.4; 10.0) and 24 (9.2, CI 6.4; 12.8) and between ALD 0.1 and placebo at weeks 12
     (10.0, CI 6.8; 14.4) and 24 (11.6, CI 8.4; 14.8).
•    When considering the change in vaginal pH, statistically significant treatment differences were seen
     when comparing ALD 0.25 with placebo and ALD 0.1 with placebo at weeks 12 and 24 (p = 0.001).
SAFETY RESULTS
o     Both Activelle Low Dose regimens resulted in a very low incidence of bleeding (moderate or heavy) or
      bleeding/spotting. By cycle 6, 95% of subjects in both the ALD 0.25 and ALD 0.1 groups had no
      bleeding and 89% of subjects in both groups had complete amenorrhoea. No significant treatment
      differences were seen when comparing ALD 0.25 and ALD 0.1.
o     At screening, mean breast density assessed by digitised quantification was 22.5%, 21.3% and 20.7% for
      ALD 0.25, ALD 0.1 and placebo, respectively. After 24 weeks of treatment the values were 23.9%,
      21.1% and 21.4%, respectively. No overall treatment differences were detected between the treatment
      groups and placebo. Visual assessment according to the Wolfe classification and the percentage scale
      showed no increase in breast density after 24 weeks of treatment.
o     No changes in weight or blood pressure were reported during the 24-week trial period in the Activelle
      Low Dose treatment groups.
o     No concerns were raised in the active treatment groups by Papanicolaou smear test, transvaginal
      ultrasound findings, vital signs or physical examination findings.
o     SAEs were reported with an incidence of 3% in the safety population during the 24 weeks of the trial and
      the distribution of these events was similar in all treatment groups.
o     Cardiovascular events, which are of particular interest since the publication of the Women’s Health
      Initiative, occurred in 2% of subjects treated with ALD 0.25 and 4% of subjects treated with ALD 0.1,
      which was lower than in the placebo group (6%). One patient died of a myocardial infarction but this
      patient was in the placebo group.
o     Clinically important symptoms relating to the breast (breast discomfort, breast pain and tenderness) were
      each reported by ≤ 2% of subjects treated with Activelle Low Dose, which was comparable with the
      placebo group. One subject in the ALD 0.25 treatment group was diagnosed with breast cancer during
      the course of the trial. A causal relationship of this case of breast cancer with the study drug cannot be
      assessed, because the study duration was only 6 months.
o     The trial drop-out rate was very low with 94% of subjects in the ALD 0.25 group and 91% of subjects in
      the ALD 0.1 group completing the trial compared to only 80% in the placebo group. AEs were recorded
      as a reason for withdrawal in 2% of subjects treated with ALD 0.25, in 6% of subjects treated with ALD
      0.1, compared with 8% in the placebo group.
o     Both Activelle Low Dose combinations showed neutral to favourable changes in lipid and lipoprotein,
      haemostasis parameters and glucose metabolism over the observation period.
Activelle Low Dose                                                        Date:                 12 January 2006    Novo Nordisk
Trial ID: ALD-1537                                                        Version:                           2.1
Integrated Clinical Trial Report                                          Status:                          Final
Report Synopsis                                                           Page:                           6 of 6

CONCLUSIONS
•    Activelle Low Dose treatment using 0.5 mg estradiol in combination with 0.1 mg or 0.25 mg
     norethisterone acetate resulted in a similar reduction in the mean number of hot flushes per week for the
     duration of the trial, and showed statistically significantly better efficacy than placebo from week 3
     onwards.
•    Activelle Low Dose treatment using 0.5 mg estradiol in combination with 0.1 mg or 0.25 mg
     norethisterone acetate resulted in a similar reduction in the severity of hot flushes per week for the
     duration of the trial, and showed statistically significantly better efficacy than placebo from week 3
     onwards.
•    Activelle Low Dose treatment at both doses demonstrated a statistically significant and clinically relevant
     effect on the Hot Flush Weekly Weighted Score (from week 4) and the Greene Climacteric Scale (from
     week 4).
•    Statistically significant differences associated with both Activelle Low Dose treatment regimens were
     seen in Maturation Value (at weeks 12 and 24) and vaginal pH (at weeks 12 and 24).
•    Generally the bleeding profile was very favourable and comparable for the ALD 0.1 and ALD 0.25
     treatment groups throughout the trial.
•    Activelle Low Dose treatment was not associated with any changes in mammographic density, when
     assessed by digital quantification and visual classification.
•    No concerns were raised in the active treatment groups by Papanicolaou smear test, transvaginal
     ultrasound findings, vital signs or physical examination findings.
•    Six months treatment with both Activelle Low Dose formulations showed a similar safety profile
     between the two regimens, with both being safe and well tolerated by the study participants.
The trial was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice.

				
DOCUMENT INFO
Shared By:
Categories:
Tags:
Stats:
views:6
posted:2/24/2012
language:
pages:6