Intrinsa
(Testosterone Transdermal System)
NDA 21-769
Indication
“Treatment of hypoactive sexual desire disorder in
surgically menopausal women receiving concomitant estrogen therapy.”
“Hypoactive sexual desire disorder (HSDD) is the persistent
or recurrent deficiency or absence of sexual thoughts, fantasies, and/or desire
for or receptivity for sexual activity, which causes personal distress or
interpersonal difficulties. Low sexual
desire may be associated with low sexual activity, sexual arousal problems or
orgasm difficulty.”
Dosing regimen:
One patch (300 mcg/day) applied to abdomen twice weekly on a
continuous basis. Patch should be replaced with a fresh patch every three to
four days.
Review by the Division of Reproductive and Urologic Drug
Products
November 3, 2004
Table of Contents
1 baCKGROUND..................................................................................................................................................... 5
1.1 Definition of FSD................................................................................................................................... 5
1.1.1 Hypoactive
Sexual Desire Disorder.................................................................................................... 5
1.2 FDA Guidance.......................................................................................................................................... 5
1.3 Agreements with Applicant......................................................................................................... 5
2 Clinical development............................................................................................................................... 5
2.1 Testosterone Therapy for HSDD................................................................................................ 5
2.2 Applicant’s Early Clinical
Development Program....................................................... 5
2.3 Dose Selection....................................................................................................................................... 5
2.4 Instrument Development and
Validation.......................................................................... 5
2.5 Overview of Clinical Trials.......................................................................................................... 5
3 Clinical Trial Design................................................................................................................................. 5
3.1 Description of Phase 2 Trial
Protocols................................................................................ 5
3.2 Description of Phase 3 Trial
Protocols................................................................................ 5
3.3 Inclusion/Exclusion Criteria....................................................................................................... 5
3.3.1 Inclusion
Criteria................................................................................................................................... 5
3.3.2 Exclusion Criteria.................................................................................................................................. 5
3.4 Schedule of Assessments............................................................................................................... 5
3.5 Endpoints & Statistical Analysis............................................................................................ 5
3.5.1 Primary
Endpoint................................................................................................................................... 5
3.5.2 Principal Secondary Endpoints........................................................................................................... 5
3.5.3 Primary Analysis..................................................................................................................................... 5
4 Clinical Trial Outcomes........................................................................................................................ 5
4.1 Enrollment............................................................................................................................................. 5
4.2 Demographic Data - Combined Trials.................................................................................... 5
4.3 Discontinuation (withdrawal) Rates.................................................................................. 5
4.4 Efficacy Outcomes............................................................................................................................. 5
4.4.1 Baseline
Findings................................................................................................................................... 5
4.5 Primary Efficacy Outcome (total SSEs
at Week 24)....................................................... 5
4.6 Principal Secondary Endpoints.................................................................................................. 5
4.6.1 Change in Personal Distress................................................................................................................ 5
4.6.2 Change in Sexual Desire....................................................................................................................... 5
4.7 Summary of Phase 3 Efficacy Findings................................................................................... 5
4.8 Secondary Analyses of Primary and
Principal Secondary Endpoints............ 5
4.8.1 Responder Analyses................................................................................................................................ 5
4.8.2 Onset of Treatment Effects:.................................................................................................................... 5
4.9 Persistence of Treatment Effect.............................................................................................. 5
4.10 Study CMK#US030993 (Minimally Important Clinical Differences)...................... 5
4.11 Summary of Efficacy and Related Issues........................................................................... 5
5 Safety................................................................................................................................................................... 5
5.1 Overview of Safety Concerns with
Testosterone......................................................... 5
5.2 Overview of Safety Database..................................................................................................... 5
5.2.1 Studies
Included...................................................................................................................................... 5
5.2.2 Demographics
of Safety Population.................................................................................................... 5
5.2.3 Safety
Outcomes Evaluated................................................................................................................... 5
5.3 Findings from Clinical Trials..................................................................................................... 5
5.3.1 Safety
Findings –Testosterone vs. Placebo........................................................................................ 5
5.3.2 Safety
Findings with Increasing Duration of Testosterone Exposure (Open Label and
Extension Phases) 5
5.3.3 Frequency
and Incidence of Selected Adverse Events (Weeks 0-78)............................................ 5
5.3.4 Relationship
of Serum Free Testosterone Levels to Androgenic Adverse Events....................... 5
5.3.5 Pharmacokinetics
of Free and Total Testosterone........................................................................... 5
5.3.6 Special
Safety Studies............................................................................................................................ 5
5.4 Summary of Overall Safety........................................................................................................ 5
5.4.1 Special
Concerns.................................................................................................................................... 5
5.4.2 Unknown
Risks........................................................................................................................................ 5
6 Pharmacovigilance Program............................................................................................................. 5
Appendices
Appendix 1 FDA Draft Guidance for Industry: Female Sexual Dysfunction – Clinical Development of Drug
Products for Treatment
Appendix 2 Applicant's Instruments to Assess Sexual Desire and
Personal Distress
Appendix 3 Listing of Limits for Markedly Abnormal Laboratory
Values
Appendix 4 Publications
Table of Tables
Table 1 Regulatory Activity........................................................................................................................... 5
Table 2
Instruments Used to Measure Response to Treatment............................................... 5
Table 3 List
of Controlled, Blinded Efficacy Studies..................................................................... 5
Table 4
Schedule of Visit Procedures: Phase 3 Trials...................................................................... 5
Table 5
Phase 3 Trial Enrollment and Completion.......................................................................... 5
Table 6
Subject Disposition: Combined Data from Four Double Blind Studies with
24 Weeks of Testosterone Exposure.................................................................................................................................................. 5
Table 7
Number of Satisfactory Sexual Events................................................................................ 5
Table 8
Change in Personal Distress Scores......................................................................................... 5
Table 9
Change in Sexual Desire Score...................................................................................................... 5
Table 10
Changes in Frequency of SSEs, and Sexual Desire and Personal Distress
Scores 5
Table 11
Responder Analysis for Change in SSEs at Week 24....................................................... 5
Table 12 Responder Analysis for Change in Sexual Desire
at Week 24................................. 5
Table 13
Distribution of Changes from Baseline in SSEs............................................................... 5
Table 14
Persistence of Treatment Effect............................................................................................. 5
Table 15
Changes from Baseline in TTS and Placebo Subjects Combined Based on the
Subject's Assessment of Clinical Benefit.................................................................................................................................. 5
Table 16
Changes in Frequency of SSEs, and Sexual Desire and Personal Distress
Scores 5
Table 17
Demographic Data for Integrated Safety Population............................................. 5
Table 18
Studies 068, 092, 133 & 134: Most Common Adverse Events (≥ 2%) During
Double Blind Phase 5
Table 19
Studies 068, 092, 133 & 134:
Adverse Events Considered Possibly or Probably Drug-Related in Double
Blind Phase............................................................................................................................................ 5
Table 20 Studies
068, 092, 133 & 134: Androgenic AEs
in Double Blind Phase............................ 5
Table 21
Studies 133 & 134: Changes in
Lipid Profile in Double Blind Phase.......................... 5
Table 22
Studies 133 & 134: Proportion
of Subjects with Markedly Abnormal Values on Lipid Profiles in Double Blind
Phase........................................................................................................................... 5
Table 23
Studies 133 & 134: Changes in
Hepatic Function in Double Blind Phase.............. 5
Table 24
Studies 133 & 134: Changes in
Carbohydrate Metabolism Markers during Double Blind Phase 5
Table 25
Studies 133 & 134: Proportion
of Subjects with Markedly Abnormal Values on Carbohydrate Metabolism Markers in
Double Blind Phase................................................................... 5
Table 26
Studies 133 & 134: Changes in
Hemoglobin in Double Blind Phase........................... 5
Table 27
Study 133: Changes in Coagulation
Parameters in Double Blind Phase......... 5
Table 28
Study 133: Proportion of Subjects
with Markedly Abnormal Values on Coagulation Parameters in Double Blind Phase........................................................................................................................... 5
Table 29
Studies 133 & 134: Most
Common Adverse Events (Incidence ≥ 2%) During Open Label Phase 5
Table 30 Studies
133 & 134: Most Common Adverse
Events (≥ 2% Incidence Rate) During Extension Phase 5
Table 31
Studies 133 & 134: Changes in
Lipid Profile in Open Label Phase............................... 5
Table 32
Studies 133 & 134: Proportion
of Subjects with Markedly Abnormal Values on Lipid Profiles in Open Label Phase........................................................................................................................................... 5
Table 33
Studies 133 & 134: Changes in
Lipid Profile in Extension Phase................................. 5
Table 34
Studies 133 & 134: Proportion
of Subjects with Markedly Abnormal Values on Lipid Profiles in Extension Phase................................................................................................................................. 5
Table 35
Studies 133 & 134: Changes in
Hepatic Function in Open Label Phase................... 5
Table 36
Studies 133 & 134: Changes in
Hepatic Function in Extension Phase..................... 5
Table 37
Studies 133 & 134: Changes in
Carbohydrate Metabolism Markers in Open Label Phase 5
Table 38
Studies 133 & 134: Proportion
of Subjects with Markedly Abnormal Values in Carbohydrate Metabolism Markers in
Open Label Phase........................................................................ 5
Table 39
Studies 133 & 134: Changes in
Carbohydrate Metabolism Markers in Extension Phase 5
Table 40 Studies
133 & 134: Changes in Hemoglobin in
Open Label Phase................................ 5
Table 41
Studies 133 & 134: Changes in
Hemoglobin in Extension Phase................................. 5
Table 42
Study 133: Changes in Coagulation
Parameters in Open Label Phase.............. 5
Table 43
Study 133: Proportion of Subjects
with Markedly Abnormal Values in Coagulation Parameters in Open Label Phase................................................................................................................................ 5
Table 44
Incidence of Adverse Events by Duration of Testosterone Exposure.............. 5
Table 45
Frequency of Adverse Events by Duration of Testosterone Exposure............ 5
Table 46
Incidence of Androgenic AE by Serum Free Testosterone Quartiles in
Double Blind Phase 5
Table 47
Studies 133 & 134: Free and
Total Testosterone Concentrations........................ 5
Table 48
Percent of Subjects with Free and Total Testosterone Levels Beyond
Normal Range for Reproductive Aged Women.......................................................................................................... 5
Table 49
Percent Ki67 Positive Cells in Subjects with Paired Samples................................... 5
Table 50
Change in Mammographic Breast Density......................................................................... 5
Table 51
Mammographic Breast Density at Baseline..................................................................... 5
Table of Figures
Figure
1 Change
from Baseline in 4-week Frequency of SSEs at Week 24.............................. 5
Figure 2 Change
from Baseline in Personal Distress Scale at Week 24 (LOCF).................. 5
Figure
3 Change
from Baseline in Sexual Desire at Week 24 (LOCF).......................................... 5
Figure
4 Time Course of Mean Differences
between TTS & placebo......................................... 5
The proposed indication for the transdermal testosterone
system is for the “treatment of hypoactive sexual desire disorder in surgically
menopausal women receiving concomitant estrogen therapy.”
Over the years, there has been uncertainty as to exactly
what constitutes a female sexual disorder or dysfunction (FSD). The World Health Organization's International Statistical Classification of
Diseases and Related Problems (ICD-10) suggests that sexual dysfunctions
are "the various ways in which an individual is unable to participate in a
sexual relationship as he or she would wish." The main categories of sexual dysfunction
include lack of sexual desire, sexual aversion disorder, failure of genital
response (arousal disorder), orgasmic dysfunction, dyspareunia, and excessive
sexual drive. The DSM-IV suggests that
sexual dysfunctions are "disturbances in sexual desire and in the
psychophysiologic changes that characterize the sexual response cycle and cause
marked distress and interpersonal difficulty." The dysfunctions include hypoactive sexual
desire, sexual aversion, female arousal disorder, female orgasmic disorder,
dyspareunia, and vaginismus.
In 1999, the new American Foundation of Urologic Disease
(AFUD) FSD diagnostic and classification system was proposed. The AFUD definitions state that disorders
must be associated with personal distress, and may be either acquired or
lifelong (chronic). The many causes of
FSD can be broadly categorized into the following: vascular, neurological,
psychogenic, and hormonal-endocrine. The
diagnosis of FSD, according to AFUD, requires the clinician to obtain a
detailed patient history that defines the problem and identifies causative or
confounding conditions and important psychosocial information. The presence of more than one dysfunction
should be explored as considerable interdependence may exist. The 4 major components of FSD according to
the AFUD classification are the following:
1. Sexual
desire disorder [hypoactive sexual desire disorder, HSDD]
2. Sexual
arousal disorder [FSAD]
3. Orgasmic
disorder [FSOD]
4. Sexual
pain disorder [no common acronym]
Hypoactive sexual desire disorder (HSDD), the proposed
indication for Intrinsa, is the persistent or recurring deficiency (or absence)
of sexual fantasies, thoughts and/or desire for, or receptivity to, sexual
activity, which causes personal distress. The cause may be either physiological
or psychological or a combination of both.
Common physiological etiologies include hormone deficiencies,
medications, and surgical interventions.
Any disruption of the female hormonal milieu caused by these etiologies
can result in decreased sexual desire.
The lack of, or a decrease in, sexual desire may also be secondary to
poor sexual arousal and response, or to pain associated with sexual
activity. HSDD is sometimes a
psychologically or emotionally based problem that can result from a variety of
reasons, including a history of sexual abuse or trauma. For instance,
depression and the treatment of depression are common problems in women with
low sexual desire. Another factor may be
difficulty with inability to attain or maintain sufficient sexual excitement, a
condition known as female sexual arousal disorder (FSAD).
In May 2000 the FDA distributed the first draft guidance for
industry for the "Clinical Development of Drug Products for FSD" (see
Appendix 1). Although the definition of
FSD was continuing to evolve at that time (and still is evolving), emphasis was
placed on clearly defining the component or components of FSD that would be
targeted for developing therapies and the potential subgroups (e.g., age,
premenopausal vs. menopausal; different hormonal therapy) that might respond
differently to therapy. Relatively
strict inclusion and exclusion criteria were encouraged. The guidance states that personal distress
should be measured to ensure appropriate patient selection for trial
participation but should not serve as the primary endpoint for establishing
effectiveness.
FDA Guidance
recommendations for the clinical development program and clinical trial design
for FSD therapies included the following:
1. Instruments,
questionnaires, scales that are used for diagnosis and endpoints should be
developed, tested, and validated in women with FSD and should be able to
differentiate between normal women and women with different components of FSD
2. Primary
endpoints should be statistically significant and clinically meaningful
over time and related to the components of FSD being studied
3. The
primary endpoint should include change in the number of satisfactory sexual
events over time [from baseline to end of treatment] compared to placebo
4. Sexual
events or encounters include:
a) satisfactory sexual intercourse
b) sexual intercourse resulting in
orgasm
c) oral sex resulting in orgasm
d) partner-initiated or self
masturbation resulting in orgasm
5. Endpoints
based on health-related quality of life (HRQL) claims should be linked to
clinically meaningful objective endpoints
6. Two
controlled Phase 3 trials of 6 months treatment duration should be conducted to
support an NDA
7. Pre-treatment
baseline assessment period of 4-8 weeks
8. Use
of a daily diary to record all sexual activities
Table 1 below is a brief tabular summary of the major
interactions between the Division and Procter and Gamble Pharmaceuticals, Inc.
(P&GP). Instrument development and
validation were completed for the 3 most important endpoints in the Phase 3
trials. Issues that were raised by the
Division at the end-of-Phase 2 meeting, with the Phase 3 protocols, and at the
pre-NDA meeting were addressed by the Applicant. The Applicant conducted their
development program consistent with the Division's May 2000 draft guidance and
subsequent advice from the Division. The
following were key issues that were raised in discussions with the Applicant:
1. Conducting
the Phase 3 trials primarily in the U.S., because of the concern for major
cultural differences in female sexuality in non-U.S. countries.
2. Establishing
and validating the diagnosis of HSDD separate from the other major components
of FSD
3. The
importance of establishing a minimally important clinical difference (MICD) to
support the primary endpoint and to help define the responder analysis
4. Meeting
the ICH guideline for long-term exposure; adding follow-up visits for safety
after treatment ends
5. Need
for a responder analysis as a secondary analysis to support the primary
endpoint analysis
6. Handling
missing data; the last observation carried forward (LOCF) method was changed to
satisfy the Division
7. Need
for additional assessments of androgenic effects, including virilization and voice
changes
Table
1
Regulatory Activity
|
IND #59, 232 (Procter & Gamble Pharmaceuticals,
Applicant)
|
|
Date
|
Topic
|
|
16 Jul 99
|
Applicant Pre-IND meeting (IND
#59,232)
|
|
8 Dec 99
|
Telecon re instrument validation and
Phase 2 protocol
|
|
5 Dec 01
|
End-of Phase 2 (EOP2) meeting; fax
to Applicant on 30 Nov 01
|
|
3 Apr 02
|
FDA response to Applicant follow-up
to EOP2 meeting (letter)
|
|
5 Aug 02
|
FDA comments on Phase 3 protocols
(letter)
|
|
11 Dec 02
|
FDA feedback on tradename and
validation of diagnosis of HSDD (letter)
|
|
26 Jun 03
|
Pre-NDA meeting
|
|
21 Jun 04
|
NDA received
|
It has been reported in
several national U.S. surveys that the proportion of menopausal women having
low sexual desire (HSDD) ranges from 7-33%.
Testosterone levels in populations of menopausal women with and without
low libido have shown overlapping ranges of levels regardless of the libido
status. Testosterone levels alone have
not been shown to have a predictable value for diagnosing HSDD or
characterizing the severity of the condition. As noted earlier, HSDD is
diagnosed by a careful medical and psychosocial history, symptoms, and the
associated distress.
In the 1980s and 1990s
there were a few reports of small studies using intramuscular or subcutaneous
testosterone to treat HSDD in menopausal women.
Treatment resulting in increased sexual desire and sexual activity as
measured by non-validated instruments for sexual function was often associated
with supraphysiologic serum testosterone levels.
Because there was no
approved therapy available for this indication, the Applicant embarked on a
clinical program to develop a testosterone transdermal system (TTS) for the
treatment of HSDD in surgically menopausal women. A transdermal delivery was selected for its
ability to deliver a relatively steady dose of testosterone that is not
affected by first pass effects of liver metabolism. The pharmacokinetics (PK) of
testosterone from the transdermal system were evaluated in single and multiple
dose studies, in standard PK and population PK studies, for durations of 4 days
to 12 months, at different application sites (abdomen or buttocks), over a
range of testosterone doses. Overall,
there were 3 bioavailability and 3 PK studies.
In Phase 2 studies, the
Applicant investigated a range of doses.
The 150 mcg/day dose was not effective, and the 450 mcg/day dose
provided no clear benefit beyond that of the 300 mcg/day dose. Based on these observations, the Applicant
selected a dose of 300 mcg/day for their Phase 3 clinical trials.
Following the FDA’s
Guidance on FSD, which states it is important to use validated instruments for
assessing responses to FSD therapy in specific target populations, the
Applicant developed three psychometric instruments for use in surgically
menopausal women in the US, Canada, Europe and Australia. These instruments were designed to measure
efficacy endpoints in women with HSDD in surgically and naturally menopausal
women. Table 2 lists these 3 instruments.
Table
2 Instruments Used to Measure Response to
Treatment
The FDA Draft Guidance stresses that the primary
endpoint for assessing the effectiveness of therapies for FSD is the number of
satisfactory sexual events. The number
of satisfactory events, the primary endpoint of the Applicant’s two major Phase
3 trials, was assessed using the Sexual Activity Log (SAL). The SAL is a record of sexual activity from the previous 7 days. The determination of "satisfaction"
was made by the subject herself, rather than by her partner or a
clinician. The completed weekly diary
was collected every 4 weeks (from the preceding 4 weeks) throughout the 24-week
trials.
The Profile of Female Sexual Function (PFSF) contains 37 questions that
measure subjective aspects of HSDD in the 7 separate domains listed in the
table. The number of questions per
domain ranges from 9 for Desire to 3 for Arousal and Concerns. The Personal Distress Scale (PDS) contains 9
items in a single domain and measures personal distress associated with a
patient's lack of interest in sex. Based
on the subject’s experience and feelings over the preceding 30 days,
subjects filled out the PFSF and PDS at Weeks 0, 4, 8, 12, and 24 in the Phase
3 trials. The PFSF and PDS scores for
each domain were then normalized so that they ranged from 0-100. Scores of 0, 20, 40, 60, 80, and 100 for each
domain correspond, on average, to the following categories of response:
"Never," "Seldom," "Sometimes,"
"Often," "Very Often," and "Always,"
respectively. A decrease in the PDS
score indicates a decrease in a subject's distress.
Based on their
validation study, the Applicant believes that the 3 instruments were shown to
be valid, consistent, and reliable for the measurement of HSDD in both
naturally and surgically menopausal women.
Appendix 2 contains the PDS and
the items from the Desire domain of the PFSF.
The clinical program to
evaluate the efficacy of TTS in the treatment of HSDD in surgically menopausal
(SM) women consisted of seven trials (see Table 3),
two of which evaluated multiple dose levels.
The two Phase 2b and the two Phase 3 trials were
similar in design and used the three instruments developed by the Applicant in
surgically menopausal women. The two blinded, placebo-controlled Phase 3
studies (2001133 and 2001134) were the major studies submitted to support
efficacy and safety. They each enrolled
over 500 women. These studies were conducted utilizing the 300 microgram dose
identified as the optimal dose in the earlier Phase 2b studies.
There were two special
studies linked to the Phase 3 trials. A
subset of 132 subjects (68 placebo and 64 active treatment) from the Phase 3
24-week studies was evaluated in a clinical relevance study (CMKUS030993) to
determine whether they experienced meaningful benefits during study
participation. The goal of this
sub-study was to determine the minimally important clinical difference (MICD)
for several parameters. The open label extension studies each included a
blinded 13-week "withdrawal study" from weeks 52-65 to evaluate the
persistence of treatment effect in a total of 205 women. All were positive responders on active
treatment during weeks 24-52 (see Section 4.9).
Table
3 List of Controlled, Blinded Efficacy Studies
|
Study
Phase/ #
|
N @
Testosterone dose (mcg/day)
|
N @ Placebo dose
|
Estrogen
Therapy
|
Comments
|
|
II a T96006
|
N= 75 @ 150
N= 75 @ 300
|
N= 75
|
Oral CEE
|
12 wk @ each dose;
crossover
|
|
II b 1999068
|
N= 107 @ 150
N= 110 @ 300
N= 111 @ 450
|
N= 119
|
Oral only
|
300 mcg/day was the
lowest, safest effective dose
|
|
II b 1999092
|
N= 37 @ 300
|
N= 39
|
Transdermal only
|
Small European study
|
|
III 2001133
|
N= 283 @ 300
|
N= 279
|
Oral and transdermal
|
24-week pivotal
|
|
III 2001134
|
N= 266 @ 300
|
N= 266
|
Oral and transdermal
|
24-week pivotal
|
|
Sub-studies of 2001133 and 2001134
|
|
|
|
|
CMK030993 Exit interview study
|
N= 64 @ 300
|
N= 68
|
Oral and transdermal
|
Meaningful Rx benefit
(MICD)*
|
|
Withdrawal study
|
N= 102 @ 300
|
N= 103
|
Oral and transdermal
|
Persistence of Rx benefit-
withdrawal
|
|
Total
|
N= 771@ 300**
|
N= 778
|
|
|
Safety of the
testosterone transdermal system (TTS) was monitored in clinical trials for
periods of 6 months (957 subjects) and 12 months (494 subjects) as described in
the safety section of this review. After the completion of the two Phase 3
12-month trials, P&G has elected to conduct long-term safety surveillance
(open-label) of subjects treated with TTS for up to an additional 3 years. This surveillance is currently on-going (321
women are enrolled beyond 12 months).
Study 1999068 was a randomized, double blind, placebo-controlled
multicenter trial investigating the effects of three TTS doses on sexual
outcome measures using the SAL and PFSF.
The 447 subjects had all undergone a hysterectomy and oophorectomy and
had low libido. The study consisted of a
8-week pre-treatment period followed by a 24-week efficacy period and a 28-week
safety extension period. Routine
laboratory and androgen/estrogen hormonal levels were followed from baseline
through the 24 weeks.
Study 1999092 was a randomized, double blind,
placebo-controlled multicenter trial investigating the effects of 300 mcg/day
on sexual outcome measures using the SAL and PFSF. The 77 subjects had all undergone a
hysterectomy and oophorectomy, had low libido, and were on transdermal estrogen
therapy (ET). The study consisted of a
8-week pre-treatment period followed by a 24-week efficacy period. Subjects were stratified into 2 groups prior
to randomization based on their dose of ET (≤0.05 mg, >0.05 mg). Routine laboratory and androgen/estrogen
hormonal levels were followed from baseline through the 24 weeks.
The two Phase 3
studies were nearly identical in design (clinical laboratory tests differed
slightly between the studies). Each was
a multicenter, multinational study conducted in SM women with HSDD. Each was based on a 24-week, randomized,
double-blind (DB), placebo-controlled (PC), parallel-group design to assess
efficacy and safety. Each was followed
by a 28-week open label (OL) extension period to assess safety.
Subjects were stratified based on their use of oral or
transdermal ET. Within each stratum,
subjects were randomly assigned in a 1:1 ratio to receive 300 mcg/day TTS or a
placebo patch. Subjects applied the
investigational TTS to their abdomen twice weekly (each patch was worn for
approximately 3-4 days). Upon completion
of the 24-week DB efficacy and safety period of the study, subjects receiving
placebo were switched to 300 mcg/day TTS, while the active cohort remained on
active treatment. The subjects and
study site personnel remained blinded to the initial randomized treatment
throughout the open label portion of each study.
The primary
objective of each study was to assess the efficacy of 300 mcg/day TTS in
treating HSDD in SM women on concomitant oral or transdermal estrogen
therapy. Efficacy was assessed by the
change in the 4-week frequency of total satisfying sexual events (SSEs) from
baseline to Week 24. Key secondary
objectives were:
1.
personal distress as measured by the
PDS score
2.
sexual desire as measured by the PFSF
The frequency of satisfactory sexual events was recorded
on the SAL that was completed by subjects at home on a weekly basis and
returned to the clinical sites at the next scheduled visit. The PFSF and PDS were completed at the
clinical sites at baseline (Week 0) and Weeks 4, 8, 12, and 24. Safety was evaluated by monitoring adverse
events (AEs), routine clinical laboratory measurements, vital signs, and
physical examinations. Skin appearance
at the most recent abdominal patch application site was evaluated at each
clinic visit for patch site symptoms of irritation. Objective assessments of androgenic effects
on the skin (increases in hair growth at the lip and chin, facial depilation,
and degree of facial acne vulgaris) were also evaluated in each study. Serum samples were analyzed in each study at
baseline and Weeks 12 and 24 for determination of free, total, and bioavailable
testosterone, SHBG, free and total estradiol, and estrone.
Inclusion criteria were developed to ensure that subjects entering the study were
surgically menopausal, satisfied major diagnostic criteria for acquired
(not chronic) HSDD, and were in stable relationships in which partner factors
would not preclude the possibility of demonstrating a treatment effect.
Women were
screened for study participation according to the following inclusion criteria
at Week -8 (Visit 1) unless otherwise specified. Eligible women must have:
1)
been 20 to 70 years old and in
generally good health based on medical history, physical examination, and
laboratory evaluation;
2)
undergone bilateral
salpingo-oophorectomy and hysterectomy at least 6 months prior to screening and
had no physical impediment to sexual function for at least 3 months prior to
screening (documented evidence of
surgery had to be provided). If the
surgical report was not available, a history consistent with removal of both
ovaries was to be obtained. Attempts to
obtain the surgical report were documented;
3)
been receiving a stable dose of ET for
at least 3 months prior to screening with the intention of maintaining that
regimen.
·This treatment should have resulted in, on average, less than 3 moderate
to severe hot flashes per day.
·Acceptable therapies included approved oral estrogens and approved
transdermal estrogen patch regimens.
·Compounded estrogen preparations, selective estrogen receptor modulators
(SERMs), or phytoestrogens preparations were not to be substituted for
the ET requirement;
4)
been, in her own judgment, in a stable
monogamous sexual relationship that was perceived to be secure and
communicative, for at least 1 year prior to study entry. The relationship was to be with the same
partner who was sexually functional, both psychologically and physically, and
expected to be physically present (i.e.,
available for sexual activity at some time during a 24-hour day) at least 50%
of each month during the 8-week pretreatment and 24-week efficacy period of the
study;
5)
answered affirmatively to ALL five of
the following questions:
1.
Before your ovaries were removed,
would you say that in general, your sex life was good and satisfying?
2.
Since your ovaries were removed, do
you feel you have experienced a meaningful loss in your level of desire for
sex?
3.
Since your ovaries were removed, do
you feel you have experienced a significant decrease in your sexual activity?
4.
Are you concerned about or bothered by
your current level of desire for or interest in sex?
5.
Would you like to see an increase in
your level of interest in or desire for sex and sexual activity?
6)
if ³ 40 years of age,
had a clinically acceptable screening bilateral mammogram (no evidence of
malignancy) as determined by the local radiologist (subjects could have
submitted a mammogram done up to 2 months prior to screening). Subjects under 40 years of age at screening
could have elected to have mammograms if they wished, but these were not
required for study entry;
7)
had a clinically acceptable Pap smear
as read by a central cytology facility (no evidence of malignancy or squamous
intraepithelial lesions) if the cervix was present. A Pap smear at study entry
could have been performed on subjects without a cervix at the discretion of the
investigator;
Exclusion criteria were
developed to ensure that psychological or physical factors, other than low
testosterone, that could cause hypoactive sexual desire were not present. Potential study subjects with medical
conditions that might cause them to be at increased risk for adverse events
(AEs) were also excluded, as were subjects taking drugs or nutritional supplements
that were likely to affect sexual function.
Women were screened for study participation according to
the following exclusion criteria at Week -8 (Visit 1) or as specified. Eligible women must not:
1)
have had dyspareunia not alleviated by
lubricants, any physical limitations, or sexual trauma since their oophorectomy
that would have interfered with normal sexual function;
2)
have been experiencing any chronic or
acute life stress relating to any major life change, such as recent loss of
income or the death of a close family member, that could have, in the opinion
of the investigator, significantly interfered with sexual activity;
3)
have had significant psychiatric
disorder (including mild depressive disorder, as evidenced by a score of ³ 14 on the Beck Depression Inventory-II [BDI-II]), or had a significant
alcohol or drug dependency and/or been receiving pharmacologic treatment for
such illness or disorder;
4)
have had evidence of clinically
significant organic disease on the history and/or physical examination that
would have, in the opinion of the investigator, prevented the patient from
completing the study, or otherwise affected the outcome of the study. Subjects could not have had any major
illness, active gallbladder disease, gynecological or breast surgery, including
excisional biopsies, within the last 6 months;
5)
have used within the last 12 weeks any
medications/preparations that could have affected sexual function or otherwise
interfered with interpretation of study results.
6)
have used tablet or powder forms of
phytoestrogens for less than 12 weeks prior to Week -8 (Visit 1). No use or stable use of phytoestrogens for 12
weeks or longer was acceptable;
7)
have used (averaging more than once a
week) in the past 30 days the following preparations: dehydroepiandrosterone (DHEA), melatonin, or
other drugs or supplements that could have, in the opinion of the investigator,
affected sexual function;
8)
have received marketed or
investigational oral, sublingual, topical, transdermal, injectable, or vaginal
androgen therapy at any time during the past 3 months, or investigational
implantable androgen therapy at any time in the past 7 months;
9)
have had current severe dermatological
problems (e.g., severe or cystic acne) or had a known or suspected
hypersensitivity or allergy to any adhesive or any of the constituents of the
transdermal systems;
10)
have had a history of breast cancer or
estrogen-dependent neoplasia (e.g., endometrial cancer) or any gynecological
cancer at any time before study entry or other cancer (except basal or squamous
cell carcinoma) within the last 5 years;
11)
have had diabetes, a history of
cerebrovascular disease, thromboembolic disorders, myocardial infarction, or
angina at any time before study entry or thrombophlebitis within the last 5
years;
12)
have had a thyroid-stimulating hormone
(TSH) value at screening above the upper limit of normal confirmed by a free T4
outside the normal laboratory range (subjects with an abnormal TSH, normal free
T4, and no clinical signs or symptoms of thyroid disease, with or without
replacement treatment, could have been admitted to the study);
13)
have had, in the opinion of the
investigator, clinically significant abnormal pretreatment laboratory
parameters (a single repeat assay was allowed if an assay result was
questionable) that would have materially impacted the patient’s ability to
participate in the study;
14)
have had the following laboratory
values:
· serum creatinine > 2.5 mg/dL
· serum total bilirubin ³ 2 times the upper limit of normal
· alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 times the upper limit of normal; or
15)
have previously participated in Study
1999068 or 1999092 or have participated in a clinical trial within 30 days or
received an investigational medication within 30 days (women participating in
observational studies, however, could have been included).
Division comment:
The Schedule of Visit Procedures for the Phase 3 clinical
trials is listed in Table 4.
Table 4 Schedule of Visit Procedures:
Phase 3 Trials
|
PROCEDURE
|
Screening
Period
|
Efficacy
Treatment Period
|
|
Visit 1
|
Visit 2
|
Visit 3
|
Visit 4
|
Visit 5
|
Visit 6
|
Visit 7
|
Visit 8
|
Visit 9
|
|
Wk -8
|
Wk -4
|
Wk 0
|
Wk 4
|
Wk 8
|
Wk 12
|
Wk 16
|
Wk 20
|
Wk 24
|
|
Informed Consent
|
X
|
|
|
|
|
|
|
|
|
|
Eligibility Criteria
|
X
|
X
|
X
|
|
|
|
|
|
|
|
Personal/Demographic Data
|
X
|
|
|
|
|
|
|
|
|
|
Medical, Gynecological and Drug History
|
X
|
X
|
X
|
|
|
|
|
|
|
|
Physical Examination (including breast and pelvic exam)
|
|
X
|
|
|
|
|
|
|
X
|
|
Bilateral Mammogram
|
|
X
|
|
|
|
|
|
|
|
|
Vital signs (BP, heart rate, temperature), weight
|
X
|
|
X
|
|
|
X
|
|
|
X
|
|
Cholesterol, triglycerides, LDL, HDL, glucose, hemoglobin A1c, insulin, serum chemistry , liver function tests,
hematology
|
X
|
|
|
|
|
|
|
|
X
|
|
Hormone measurements (Androgens, Estrogens and SHBG)
|
|
X
|
|
|
|
X
|
|
|
X
|
|
Hirsutism, Frequency of facial depilation, Acne score
|
|
X
|
|
|
|
X
|
|
|
X
|
|
Randomize to treatment
|
|
|
X
|
|
|
|
|
|
|
|
Review of inventories with patients
|
X
|
X
|
|
|
|
|
|
|
|
|
Collect completed SAL
|
|
X
|
X
|
X
|
X
|
X
|
X
|
X
|
X
|
|
Complete PFSF, PDS
|
|
|
X
|
X
|
X
|
X
|
|
|
X
|
|
Concomitant Medications
|
|
|
|
X
|
X
|
X
|
X
|
X
|
X
|
|
AE Adverse Events
|
X
|
X
|
X
|
X
|
X
|
X
|
X
|
X
|
X
|
|
|
|
|
|
|
|
|
|
|
|
The primary efficacy endpoint was the change from
baseline in the total frequency of
satisfying sexual events at 24 weeks (sum of the 4 consecutive weekly
frequencies on SAL questions 3 and 6 during Weeks 21-24). In this document, the frequency
of satisfying sexual events is presented as the total count over a 4-week
period.
Secondary endpoints were the sexual desire domain score of the PFSF
and the PDS Score (Distress) at 24 weeks.
Each item within a domain has 6 possible answers ranging from all of the
time to none of the time. Raw domain
scores were computed by summing the scores for items within a domain and
transforming the score to a 0 to 100 scale.
(See Section 2.4.)
The primary analysis was
based on the intent-to-treat (ITT) population.
The change from baseline
in the total frequency of satisfying sexual activity, summed over Weeks 21-24,
was regressed on treatment group, pooled center, baseline average 4 week
frequency of satisfying sexual activity, age, and ET route in an ANCOVA
analysis. Least squares estimates of the
mean 4 week frequency of satisfying sexual activity for the 300 mcg/day testosterone
arm and the placebo arm were computed, as were 95% confidence intervals and a
p-value testing the null hypothesis of no treatment differences. Secondary models, including possible
interactions (e.g., pooled center by treatment), were explored to evaluate
consistency of treatment effects across other factors.
To account for subjects
who did not complete the 24-week efficacy period of the study and therefore had
missing SAL weekly frequencies for Weeks 21-24, a last observation carried
forward (LOCF) approach was used. For
each patient, the sexual activity corresponding to the last SAL and 3 preceding
SALs was used in the analysis. For
example, if the last SAL returned from a patient is the Week 23 SAL, then the
frequency of sexual activity recorded for weeks 20-23 was used in the
analysis. To account for missing weekly
assessments within any four-week interval of follow-up, the average of
non-missing assessments was imputed for the missing assessment.
The prospectively defined analyses of the primary endpoint were not the
same in all studies. The Phase 2b
studies used Poisson regression analysis, and the Phase 3 studies used ANCOVA
and Wilcox-rank sums (WRS). The WRS was
used in the Phase 3 studies to provide appropriate comparisons between 300
mcg/day TTS and placebo in cases where the ANCOVA assumptions were
violated. Because a few influential
outliers occurred in Study 2001134, WRS was conducted for cross-study
comparisons, in addition to ANCOVA. All
efficacy analyses are based on the change from baseline in the total satisfying
sexual activity at Week 24, using the ITT population and a LOCF approach.
Phase 3 Study 2001133 enrolled 562 subjects in the U.S.,
Canada, and Australia (52 clinical sites).
A total of 451 (80%) subjects completed the efficacy and safety period
through Week 24. Of these subjects, 449 participated in the 28-week open label
period and 380 (85%) completed through Week 52.
Phase 3 Study 2001134 enrolled 533 subjects in the U.S., Canada, and
Australia (51 clinical sites). A total
of 418 (78%) subjects completed through Week 24. Of these subjects, 388 (93%) participated in
the 28-week open label period and 261 (67%) of the 388 completed through Week
52 (see Table 5).
Table
5 Phase 3 Trial Enrollment and Completion
|
Study Week
|
Study 2001133
|
Study 2001134
|
Totals
|
|
Blinded Phase
|
N
|
%
|
N
|
%
|
|
|
0 (Enrollment)
|
526
|
100%
|
533
|
100%
|
1,059
|
|
24 (Completion)
|
451
|
86%
|
418
|
78%
|
869 (82%)
|
|
Open Label Phase
|
|
|
|
|
|
|
24 (Enrollment)
|
449
|
100%
|
388
|
100%
|
837
|
|
52 (Completion)
|
380
|
85%
|
261
|
67%
|
641 (77%)
|
Demographics were similar across between the placebo and TTS
groups. In the 4 trials combined (Phase
2b and 3 studies, see Table
3) the following baseline
demographic and anthropometric data were observed among the 1,401 subjects:
1. Age:
mean 49 (7.5 SD); median 49; Min-Max 26-70
2. Age
distribution: 10% were 30-39; 41% were 40-49, 41% were 50-59; 6% 60-64
3. Race:
89% Caucasian; 6% African American; 3% Hispanic
4. Geography:
89% U.S.; 3% Canada; 4% Europe; 4% Australia
5. Marital
status: 87% married to partner; 13% not married
6. Duration
of relationship with partner (years): mean 18.6 (11.35 SD); median 17; Min-Max
1-54
7. Baseline
weight (kg): mean 73.1 (15.3 SD); median 71; Min-Max 40.6-153.6
8. Baseline
height (cm): mean 163.8 (6.38); median 163; Min-Max 132-183
9. Body
Mass Index: mean 27.2 (5.51); median 26; Min-Max 17-58
10. Estrogen
therapy route: 77% oral; 23% transdermal
11. Age
at hysterectomy: mean 39.6(7.9); median 40; Min-Max 17-66
12. Age
at oophorectomy: mean 40.4 (7.8); median 41; Min-Max 17-66
13. Years
since surgery: ~9 (7.2); median 7-8; Min-Max 0.5-42.5
14. Tobacco
use: 53% never; 30% previously; 17% currently
15. Alcohol
use: 22% never; 4% previously; 73% currently
Studies
combined: A total of 1401 subjects (704 in the placebo group;
697 in the 300 mcg/day TTS group) were enrolled in Studies 2001133 (Phase 3),
2001134 (Phase 3), 1999068 and 1999092 (both Phase 2). A similar percentage of subjects in the two
treatment groups completed these studies through Week 24. A total of 309 (22%) subjects were
discontinued during the 24-week double blind period. The most common reasons for discontinuation
were AEs (8% each) and voluntary withdrawals (7% placebo, 9% TTS) (see Table 6). Discontinuation for adverse events will be
discussed in more detail in Section 5.3.1.1
of this document.
Table
6 Subject Disposition: Combined Data from Four
Double Blind Studies with 24 Weeks of Testosterone Exposure
Individual studies: When compared among the individual studies, a
similar percentage of subjects (within 1-2%) in each treatment group in each
trial withdrew due to the 6 reasons listed above. The only exception was in Study 2001133 where
a lower percentage of subjects on placebo (12/279= 4%) voluntarily withdrew
(not due to an AE) as compared to the TTS subjects (26/283= 9%).
Discontinuation over
time: No increases in the rate
of patient withdrawals in the 4 combined studies were observed with increased
duration of exposure to 300 mcg/day TTS when comparing each 4-week time period
during the 24-week studies. The percentage
of subjects who withdrew from each of the studies was similar between the two
treatment groups for each 4-week period.
For each 4-week period, the range was 3.1-5.5% for placebo and 3.0-4.3%
for TTS. Similar results were observed
when time to withdrawal was compared between the two individual Phase 3
studies.
Mean scores at baseline: The overall mean scores at baseline in the
two phase 2 and two phase 3 studies for the SAL 4-week frequency of total
satisfying sexual events (3.0), PFSF sexual desire (21.2), and personal
distress (64.5) were consistent with mean scores from other studies with women
who considered themselves to have few satisfying sexual activities, low sexual
desire, and were distressed about their lack of sexual desire. Baseline disease severity as judged by the
three main endpoints (satisfying sexual events, distress scores, and desire
scores) was similar between the active and placebo treatment groups across the
four studies.
Estrogen formulations used: Overall, 77% of the subjects in the combined studies were taking
concomitant oral estrogen therapy (ET) and 23% were receiving concomitant
transdermal ET. Subjects who
participated in Studies 2001133 and 2001134 used either oral or transdermal
ET. Subjects in Study 1999068 used
concomitant oral ET, whereas subjects in Study 1999092 used concomitant
transdermal ET only. Of the 1,075
subjects on oral ET, the percentage of subjects taking higher dose oral ET
(defined by the Applicant as >0.625 mg Premarin or its equivalent) was 48%
and those on higher dose transdermal ET (defined by the Applicant as >0.05
mg) was 54%. The remaining subjects were receiving lower dose oral or
transdermal ET. In the oral estrogen therapy group, the percentage of subjects
taking conjugated equine estrogen (63%) and non-conjugated equine estrogen
(37%) was also similar between the two treatment groups in the 3 studies using
oral ET. The next most commonly used form of concomitant ET was estradiol.
The primary endpoint was the change in SSEs (sum of the SAL
Question 3 and 6 - satisfying sexual activity with or without
intercourse).
A discussion and analysis of the efficacy results
follows, with results from the 4 individual studies shown first, followed by
Figures (bar graphs) of the individual and combined results shown
together.
Table 7
Number of Satisfactory Sexual Events
|
Study Number
(Number of subjects)
|
Testosterone dose (mcg/day)
|
Baseline Meana
|
Mean Change from Baseline at Week 24a,b
|
Efficacy Analysis Method
|
Results
p-value
|
|
Frequency of
Total Satisfying Sexual Episodes (SSEs)
|
|
Phase 3 trials
|
|
2001133
(N=562)
|
0 (placebo)
|
2.94
|
0.98
|
ANCOVA
|
p=0.0003
|
|
300
|
2.82
|
2.13
|
|
2001134
(N=532)
|
0 (placebo)
|
3.19
|
0.73
|
Wilcoxon Rank Sumb
|
p=0.0010
|
|
300
|
3.04
|
1.56
|
|
Phase 2 trials
|
|
1999068*
(N=229)
|
0 (placebo)
|
2.8
|
1.20
|
Poisson Regression
|
p=0.0493
|
|
300
|
2.92
|
2.32
|
|
1999092*
(N=76)
|
0 (placebo)
|
3.20
|
1.12
|
Poisson Regression
|
p=0.0641
|
|
300
|
2.08
|
3.08
|
|
|
|
|
|
|
|
|
|
|
|
To be evaluable
for efficacy, a subject had to receive at least 8 weeks of blinded
treatment. The table above shows the mean
change from baseline in the SSEs for the last recorded 4-week period of
time. In both Phase 3 studies (2001133 and 2001134), compared with placebo,
subjects treated with 300 mcg/day TTS had an increase in the frequency of total
SSEs.
Mean changes from
baseline on 300 mcg/day TTS and placebo are shown in Figure 1.
Figure
1 Change
from Baseline in 4-week Frequency of SSEs at Week 24
The most important secondary endpoints were the decrease in
the personal distress score of the PDS and the increase in the sexual desire
domain of the PFSF.
The PDS measures personal distress associated with
subjects’ low desire for, and lack of interest in, sex. The PDS instrument contains 9 items in a
single domain. Subjects filled out the
questionnaire based on their experiences and feelings over the preceding 30
days. (See Section 2.4.) A decrease in the PDS score indicates a
decrease in a patient's distress.
Across the two Phase 3 trials, the baseline score for
distress ranged from 62.57 to 66.38 for the placebo group and from 64.78 to
66.61 for the TTS group, which corresponds to an average answer of "often"
being distressed for the 9 questions (see Table 8). The Least-Squares Means difference between
the change in placebo and TTS scores was approximately 7.3.
Table
8
Change in Personal Distress Scores
|
Study Number
|
Testosterone dose
(mcg/day)
|
Baseline Meana
|
Mean Change from
Baseline at Week 24a,b
|
Efficacy Analysis
Method
|
Results
p-value
|
|
Personal Distress
Score
|
|
Phase 3 studies
|
|
2001133
(N=562)
|
0
|
62.57
|
-16.31
|
ANCOVA
|
p=0.0006
|
|
300
|
64.78
|
-23.55
|
|
2001134
(N=532)
|
0
|
66.38
|
-18.27
|
ANCOVA
|
p=0.0091
|
|
300
|
66.61
|
-24.34
|
|
Phase 2 trials
|
|
1999068*
(N=229)
|
0 (placebo)
|
64.71
|
-18.46
|
ANCOVA
|
p=0.1258
|
|
300
|
65.39
|
-23.76
|
|
1999092*
(N=76)
|
0 (placebo)
|
56.73
|
-2.11
|
ANCOVA
|
p=0.0025
|
|
300
|
57.14
|
-22.10
|
|
|
|
|
|
|
|
|
|
|
|
The changes from baseline in the PDS score at Week 24
for the four individual studies and the studies combined are shown in Figure 2.
Figure
2 Change from Baseline in Personal
Distress Scale at Week 24 (LOCF)
Change in desire was assessed using the Desire domain of
the PFSF (see Section 2.4). Subjects were instructed that feelings could
be either mental or physical and could occur in the absence of sexual activity.
Their responses were to reference the past 30 days.
Across the two phase 3 trials, the baseline score for
sexual desire ranged from 20.82 to 23.37 for the placebo group and from 19.79
to 21.67 for the active treatment group.
This generally corresponds with an average answer of "seldom"
for the 9 items in the desire domain.
Table 9
Change in Sexual Desire Score
|
Study Number
|
Testosterone dose
(mcg/day)
|
Baseline Meana
|
Mean Change from
Baseline at Week 24a,b
|
Efficacy Analysis
Method
|
Results
p-value
|
|
Phase 3 trials
|
|
2001133
(N=562)
|
0 (placebo)
|
20.82
|
6.90
|
ANCOVA
|
p=0.0006
|
|
300
|
19.79
|
11.85
|
|
2001134
(N=532)
|
0 (placebo)
|
23.37
|
6.21
|
ANCOVA
|
p=0.0006
|
|
300
|
21.67
|
11.38
|
|
Phase 2 trials
|
|
1999068*
(N=229)
|
0 (placebo)
|
20.14
|
8.38
|
ANCOVA
|
p=0.0498
|
|
300
|
20.94
|
13.67
|
|
1999092*
(N=76)
|
0 (placebo)
|
19.89
|
5.98
|
ANCOVA
|
p=0.0214
|
|
300
|
23.12
|
16.43
|
|
|
|
|
The
changes from baseline in the PFSF Desire domain score at Week 24 for the four
individual studies and the studies combined are shown in Figure
3.
Figure
3 Change
from Baseline in Sexual Desire at Week 24 (LOCF)
An overview of the results for the primary and two most
important secondary efficacy endpoints for the two phase 3 clinical trials can
be found in Table 10.
Table
10
Changes in Frequency of SSEs, and Sexual Desire and Personal Distress
Scores
|
Endpoint
Study Number
|
Testosterone dose (mcg/day)
|
Baseline Meana
|
Mean Change from Baseline at Week 24a,b
|
Efficacy Analysis Method
|
Results
p-value
|
|
Frequency
of Total SSEs
|
|
2001133
|
0
|
2.94
|
0.98
|
ANCOVA
|
p=0.0003
|
|
300
|
2.82
|
2.13
|
|
2001134
|
0
|
3.19
|
0.73
|
Wilcoxon Rank Sumb
|
p=0.0010
|
|
300
|
3.04
|
1.56
|
|
Sexual
Desire Score [range 0 to 100]
|
|
2001133
|
0
|
20.82
|
6.90
|
ANCOVA
|
p=0.0006
|
|
300
|
19.79
|
11.85
|
|
2001134
|
0
|
23.37
|
6.21
|
ANCOVA
|
p=0.0006
|
|
300
|
21.67
|
11.38
|
|
Personal
Distress Score [range 0 to 100]
|
|
2001133
|
0
|
62.57
|
-16.31
|
|
|
|
300
|
64.78
|
-23.55
|
ANCOVA
|
p=0.0006
|
|
2001134
|
0
|
66.38
|
-18.27
|
|
|
|
300
|
66.61
|
-24.34
|
ANCOVA
|
p=0.0006
|
|
a For frequency of total satisfying
sexual episodes, baseline mean and mean change from baseline at Week 24 refer
to the average 4-week frequency.
b Mean change from baseline adjusted
for age, estrogen therapy route, pooled centers, and baseline value. For frequency of total satisfying episodes
in Study 2001134, the ANCOVA model assumption of normality was severely
violated; therefore, unadjusted mean change from baseline (i.e. no covariate
adjustment) is shown and Wilcoxon rank sum analysis was conducted.
|
The Applicant conducted a responder analysis
for the primary efficacy endpoint of SSEs and the secondary endpoint of change
in the desire score. The definition of a
response was based upon the Applicant’s findings from Study CMK#US030993, which
was designed to identify the minimally important clinical difference (MICD)
(see Section 4.10).
4.8.1.1
Applicant-Defined Responder Analyses
Change in Satisfactory Sexual Events Based on
the findings of Study CMK#US030993,
the Applicant concluded that an increase of 1.1 events per four weeks was the
minimally important clinical difference.
The responder analysis based on this MICD value of > 1 SSE per four
weeks is shown in Table 11
below. For each of the studies, a
greater proportion of subjects in the TTS groups were identified as having a
positive response to treatment. In the
two phase 3 studies, the difference in response rate between TTS and placebo
groups ranged from approximately 11 to 17%.
Table
11
Responder Analysis for Change in SSEs at Week 24
|
Study
|
Placebo
Sample/responders
(% responders)A
|
TTS
Sample/responders
(% responders)
|
|
2001133
|
273/95 (34.8%)
|
276/126 (45.7%)
|
|
2001134
|
255/64 (25.1%)
|
258/109 (42.2%)
|
|
1999068
|
112/43 (38.4%)
|
108/55 (50.9%)
|
|
1999092
|
37/10 (27.0%)
|
35/22 (62.9%)
|
|
Combined
|
677/212
(31.3%)
|
677/312
(46.1%)
|
|
|
Change
in Sexual Desire Based on the findings of Study CMK#US030993, the Applicant concluded that an increase of
≥ 8.9 points on a scale of 1 to 100 on the Desire domain of the PFSF was
the minimally important clinical difference.
The responder analysis based on this MICD value of ≥ 8.9 points is
shown in Table 12
below. For each of the studies, a
greater proportion of subjects in the TTS groups were identified as having a
positive response to treatment. In the
two phase 3 studies, the difference in response rate between TTS and placebo
groups ranged from approximately 15 to 17%
Table
12 Responder Analysis for Change in Sexual Desire
at Week 24
|
Study
|
Placebo
Sample/responders
(% responders)A
|
TTS
Sample/responders
(% responders)
|
|
200113
|
269/93 (34.6%)
|
269/138 (51.3%)
|
|
200134
|
257/87 (33.9%)
|
252/124 (49.2%)
|
|
1999068
|
101/40 (39.6%)
|
102/55 (53.9%)
|
|
1999092
|
35/15 (42.9%)
|
34/18 (52.9%)
|
|
Combined
|
662/235
(35.5%)
|
657/335
(51.0%)
|
|
|
4.8.1.2
FDA-Requested Responder Analysis
Distribution
of Changes from Baseline in SSEs The
Division requested a post hoc analysis showing the distribution of changes from
baseline in SSEs in the placebo and TTS groups in the two Phase 3 trials. The results are shown in Table 13.
Table
13 Distribution of Changes from Baseline in SSEs
|
|
Study 2001133
|
Study 2001134
|
|
Change category (Increase in
SSEs)
|
Placebo (N=273)
n (%)
|
TTS
(N=276)
n (%)
|
Placebo (N=255)
n (%)
|
TTS
(N=258)
n (%)
|
|
< 0 SSE
|
90 (33.0)
|
73 (26.4)
|
105 (41.2)
|
83 (32.2)
|
|
0 to <1.0
|
70 (25.6)
|
57 (20.7)
|
62 (24.3)
|
46 (17.8)
|
|
1 to <2.0
|
44 (16.1)
|
35 (12.7)
|
30 (11.8)
|
40 (15.5)
|
|
2 to <3.0
|
17 (6.2)
|
26 (9.4)
|
17 (6.7)
|
16 (6.2)
|
|
3 to <4.0
|
15 (5.5)
|
21 (7.6)
|
10 (3.9)
|
19 (7.4)
|
|
4 to <5.0
|
11 (4.0)
|
21 (7.6)
|
11 (4.3)
|
13 (5.0)
|
|
³
5
|
26 (9.5)
|
43 (15.6)
|
20 (7.8)
|
41 (15.9)
|
|
|
Overall, maximal mean differences between placebo and TTS treated
subjects for SSEs and sexual desire were observed by 12 weeks and were
maintained to 24 weeks. Mean differences
between placebo and TTS treated subjects in distress continued to decline over
the 24-week treatment period. Figure 4
below combines findings from Studies 2001133 and 2001134.
Figure
4 Time Course of Mean Differences between TTS
& placebo
The persistence of treatment effects was assessed during a
13-week double blind follow-up period (Weeks 53-65) of Studies 2001133 and
2001134. All subjects who completed both
the 24 week double blind
placebo-controlled phase and the subsequent 28 week open label TTS phase of the
two phase 3 trials were offered the opportunity to participate in a study to
evaluate persistence of treatment effect.
Subjects who agreed to participate were asked a set of questions about
their response to treatment during the previous 28-week open label period. The
subset of subjects who responded positively to specific questions, including
having experienced an increase in desire for sexual activity and an increase in
satisfying sexual activity compared with before entering the study, were
randomized in a 1:1 ratio to receive placebo or TTS in a double-blind manner
for 13 weeks. Sex therapists conducted
follow-up telephone interviews with these subjects between Weeks 63 and 65 to
assess persistence of treatment effect.
Of the 205 subjects enrolled, 199 (97%) completed interviews.
The primary endpoint in this study was the sex therapists’
assessment of a “noticeable decrease” in desire for sexual activity during the
13 week treatment period. A higher percentage of women in the placebo group
compared with TTS [62.7% vs. 43.3%] reported a “noticeable decrease” in desire
for sexual activity during the 13 week study.
In addition, a higher percentage of women in the placebo group compared
to the TTS group [47.1% vs. 25.8%] reported experiencing a decrease in the
frequency of SSEs. (See Table 14.)
Table
14 Persistence of Treatment Effect
|
Question
|
Placebo
|
TTS
|
|
|
n/N
|
%
|
n/N
|
%
|
|
Noticeable Decrease in Desire for
Sexual Activity (Therapist)
|
64/102
|
62.7
|
42/97
|
43.3
|
|
Noticeable Decrease in Desire for Sexual
Activity (Patient)
|
64/102
|
62.7
|
42/97
|
43.3
|
|
Noticeable Decrease in Overall
Clinical Benefit (Therapist)
|
62/102
|
60.8
|
45/97
|
46.4
|
|
Noticeable Decrease in Overall
Clinical Benefit (Patient)
|
64/102
|
62.7
|
40/97
|
41.2
|
|
Noticeable Decrease in Satisfying
Sexual Activity (Patient)
|
48/102
|
47.1
|
25/97
|
25.8
|
|
Noticeable Decrease in Desire to
Initiate Activity (Patient)
|
61/102
|
59.8
|
37/97
|
38.1
|
|
Noticeable Decrease in Anticipation
of Sexual Activity (Patient)
|
55/102
|
53.9
|
32/97
|
33.0
|
|
N= number of subjects with
interviews; n= number of subjects with noticeable decrease
% = n/N, percentage of subjects with
the finding
|
A clinical relevance
study was designed by the Applicant to investigate the subjects’ perspective on
the results of their study treatment during the blinded portion of studies
2001133 and 2001134. The primary
objectives of the clinical relevance study were to determine whether subjects
experienced benefits of study treatment that they considered meaningful, and to
define the magnitude of changes in selected clinical endpoints that were
associated with a meaningful treatment benefit as defined by the women
themselves.
The study data came
from a subset of women from the two Phase 3 efficacy studies. A series of 132 one-on-one patient interviews
were conducted by one trained, experienced female interviewer using a
structured interview guide that contained both open-ended and fixed-response
(yes/no or scaled-response) questions. All interviews were conducted no later
than 2 weeks after subjects completed or exited double blind treatment. The
subjects, interviewer, study site personnel, and the Applicant representatives
who observed interviews or analyzed clinical data all remained blinded to the
treatment assignments (active or placebo). Baseline demographics and disease
severity in this subset were representative of the entire group of women in the
Phase 3 studies.
The primary assessment in the clinical relevance study was based
on the subjects’ answers (yes or no) to the following question, which was asked
with reference to their experiences during the double-blind portion of the
studies:
“Considering
everything that we have talked about today, would you say that you experienced
a meaningful benefit from the study patches?”
Subjects were
dichotomized based on their answer to the above question. For each of the two groups, the mean and
median changes from baseline in the three study endpoints (satisfying sexual
activity [SSEs], personal distress, and sexual desire) were determined (see Table 15). Of the 54 subjects
reporting a meaningful benefit, 39% had received placebo and 61% TTS
treatment. Among placebo subjects, 31%
reported they had a meaningful benefit; among TTS subjects, 52% reported a
meaningful benefit.
Table 15
Changes from Baseline in TTS and Placebo Subjects Combined Based on the
Subject's Assessment of Clinical Benefit
|
Parameter
|
Experienced
meaningful benefit?
|
N
(%)
132
(100%)
|
Change from
baseline in 4-week frequency*
|
|
Mean
|
Median
|
Minimum
|
Maximum
|
|
|
|
|
|
|
SSEs
|
Yes
|
54
(41.2%)
|
4.4
|
2.26
|
-1.7
|
25.0
|
|
No
|
77
(58.8%)
|
0.5
|
0.0
|
-5.9
|
16.3
|
|
Distress
Score
|
Yes
|
54
(40.9%)
|
-36.5
|
-34.3
|
-100
|
28.6
|
|
No
|
78
(59.1%)
|
-8.8
|
-8.57
|
-51.4
|
45.7
|
|
Desire
Score
|
Yes
|
54
(40.9%)
|
21.0
|
16.7
|
-17.8
|
66.7
|
|
No
|
78
(59.1%)
|
2.9
|
2.22
|
-33.3
|
44.4
|
|
|
For the 3 endpoints examined, there was a range
of changes from baseline and there was overlap between subjects who reported a
meaningful overall benefit and subjects who reported no meaningful overall
benefit. However, all 3 endpoints in
subjects who reported an overall meaningful benefit showed mean and median
changes from baseline that were numerically greater than those in subjects who
reported no meaningful benefit.
Patient responses in this study were used to define a minimally important
clinical difference (MICD) from baseline in total satisfying activity (SSEs) and
desire scores. Using Receiver Operating
Characteristics (ROC) analysis, the MICDs were defined as the values that best
dichotomized subjects on the basis of reported
meaningful benefit. The MICDs
determined by the Applicant were:
·
an increase of > 1.0 in satisfying
sexual events per 4 weeks
·
an increase of ≥8.9 in sexual desire score
·
a decrease of at least 20 points in
distress score
These responder definitions were
applied to the Phase 3 results to examine the differences between the
percentages of responders on TTS treatment and placebo (see Section 4.8.1).
- The
appropriateness of the design of Study CMK#US030993,
- The
Applicant’s interpretation of the study findings, and/or
- The
Applicant’s values for the MICDs for the primary and principal secondary
efficacy endpoints.
The clinical development program by the Applicant followed
the May 2000 FDA Draft Guidance for industry for products being developed for a
female sexual dysfunction indication. Two
Phase 3 trials were conducted in a patient population of surgically menopausal
women with HSDD. The primary endpoint was the change in the number of
satisfactory sexual episodes (SSEs), and the two key secondary endpoints were
the change in sexual desire and personal distress scores. Three instruments were developed to record
and measure the efficacy endpoints.
Changes in the primary and secondary endpoints are
summarized in Table 16.
Table
16 Changes in Frequency of SSEs, and Sexual
Desire and Personal Distress Scores
|
Endpoint
Study Number
|
Testosterone dose (mcg/day)
|
Baseline Meana
|
Mean Change from Baseline at Week 24a,b
|
Efficacy Analysis Method
|
Results
p-value
|
|
Frequency of Total
SSEs
|
|
2001133
|
0
|
2.94
|
0.98
|
ANCOVA
|
p=0.0003
|
|
300
|
2.82
|
2.13
|
|
2001134
|
0
|
3.19
|
0.73
|
Wilcoxon Rank Sumb
|
p=0.0010
|
|
300
|
3.04
|
1.56
|
|
Sexual Desire Score
[range 0 to 100]
|
|
2001133
|
0
|
20.82
|
6.90
|
ANCOVA
|
p=0.0006
|
|
300
|
19.79
|
11.85
|
|
2001134
|
0
|
23.37
|
6.21
|
ANCOVA
|
p=0.0006
|
|
300
|
21.67
|
11.38
|
|
Personal Distress
Score [range 0 to 100]
|
|
2001133
|
0
|
62.57
|
-16.31
|
|
|
|
300
|
64.78
|
-23.55
|
ANCOVA
|
p=0.0006
|
|
2001134
|
0
|
66.38
|
-18.27
|
|
|
|
300
|
66.61
|
-24.34
|
ANCOVA
|
p=0.0006
|
|
a For frequency of total satisfying
sexual episodes, baseline mean and mean change from baseline at Week 24 refer
to the average 4-week frequency.
b Mean change from baseline adjusted
for age, estrogen therapy route, pooled centers, and baseline value. For frequency of total satisfying episodes
in Study 2001134, the ANCOVA model assumption of normality was severely
violated; therefore, unadjusted mean change from baseline (i.e. no covariate
adjustment) is shown and Wilcoxon rank sum analysis was conducted.
|
In the aftermath of the Women’s
Health Initiative (WHI) studies, of the risks and benefits of estrogen and
combined estrogen and progestin therapy in postmenopausal women, use of hormone
therapy in this population is subject to heightened scrutiny. The fact that the results of these relatively
long-term, randomized, double-blind, placebo-controlled trials were at variance
with data provided by a number of observational studies suggests that
short-term or uncontrolled studies may not provide adequate estimates of the
risks of hormonal therapy in postmenopausal women.
The
proposed indication, for use in surgically menopausal women receiving concomitant
estrogen therapy, raises two important issues that should be considered:
1.
Women who take this product will be on estrogen,
the duration and safety of which must be examined in light of the WHI
estrogen-only study in women status post hysterectomy.
2. Another
hormone, testosterone, will be added to estrogen. In the second WHI study, the
addition of progesterone to estrogen increased the risk of breast cancer and
cardiovascular effects. It is unknown
whether the addition of a different hormone, testosterone, might have similar
or unanticipated adverse effects.
The literature
provides little information about the safety of exposing postmenopausal women
to testosterone at doses that produce plasma concentrations that are within or
slightly above the range of those normally observed in reproductive aged
women. What data are available often
concern formulations or dose levels that differ from that achieved by the TTS
patch. Nonetheless, potential concerns
that have been raised in the literature include:
- Cardiovascular
safety – potentially mediated by testosterone’s effects on
- lipids
- vascular tone
- plasma viscosity
- coagulation
- polycythemia
- insulin resistance
- Androgenic
effects in women
- acne
- hirsutism
- alopecia
- voice deepening
- clitoromegaly
- Hepatotoxicity
- Effects
on mood and behavior
- Endometrial
hyperplasia and cancer
- Breast cancer
The safety database
for subjects using TTS was examined for evidence of these effects in women
treated with testosterone and estrogen therapy.
Integrated safety data from two phase 2 studies (Studies
1999068 and 1999092, hereinafter referred to as 068 and 092, respectively) and
two pivotal phase 3 trials (Studies 2001133 and 2001134, hereinafter referred
to as 133 and 134, respectively) were reviewed.
All four of these studies were 24-week, randomized, double-blind,
parallel-group, placebo-controlled trials evaluating the safety and efficacy of
a testosterone transdermal delivery system (TTS) in surgically menopausal women
with HSDD. Study 068 compared patches
that delivered doses of 0 (placebo), 150, 300 or 450 mcg/day when applied twice
weekly. Studies 092, 133 and 134
utilized a TTS which administered a daily dose of 300 mcg when applied twice
weekly.
Three of the studies continued on as safety extensions: Study 068 as a double-blind,
placebo-controlled trial for an additional 28 weeks, and Studies 133 and 134 as
open-label active treatment extensions for an additional 28 weeks. Following completion of the first year of
these studies, limited additional open-label safety surveillance data have been
obtained from subjects from Studies 133 and 134 who continued to use the TTS
for an additional 26 weeks beyond the first year, in what is planned to be a
two year safety extension. Thus, the
primary data available for safety review include:
·
A 24 week placebo-controlled phase, which enrolled 1399 subjects (696
on TTS) in four studies
·
A 28 week open label phase, which enrolled 837 subjects (all on TTS)
from the two phase 3 studies (of these, 418 had been on placebo in the double
blind phase and 419 had been on active treatment)
·
An ongoing open label safety extension phase (for which data from weeks
52-78 is currently available), which enrolled 321 subjects (all on TTS) from
the two phase 3 studies (of these, 167 previously had been treated with TTS for
28 weeks and 154 previously had been treated with TTS for 52 weeks)
An
additional special safety study was also reviewed. Study 2003082 was a 24-week, randomized,
double-blind, placebo-controlled trial which evaluated effects of the 300 mcg
TTS on mammographic breast density and breast epithelial proliferation in
naturally menopausal women also taking combined estrogen/progestogens hormone
products.
Demographic information for subjects
from the integrated safety population comprising Studies 068, 092, 133 and 134
are presented in Table
17. Demographic
data for the subjects from Studies 133 and 134 who continued into the open
label and extension phases indicate that they were representative of the safety
population as a whole.
Table
17 Demographic Data for Integrated Safety
Population
The four studies provided data on the following
safety parameters:
·
Adverse events – deaths, serious adverse events, withdrawals due to
adverse events, common adverse events
·
Androgenic effects – acne, hirsutism, alopecia, voice deepening,
clitoromegaly
·
Application site reactions (ASRs)
·
Impact on estrogen-related effects – hot flushes, breast tenderness
·
Laboratory values – serum chemistry, including lipid, renal and hepatic
panels, carbohydrate metabolism, hematology and coagulation profile
·
Vital signs and weight
Subsets
of subjects in Studies 068 and 092 also provided data on the effects of
testosterone on total body composition, bone mineral density and markers of
bone turnover, platelet aggregation, and vascular reactivity and impedance of
blood flow as measured by the vascular pulsatility index. A study in naturally menopausal women
provided data on mammographic breast density and breast epithelial
proliferation.
Deaths
There
was a single death, in a placebo subject in Study 134 during the double
blind phase of the study. Death was due
to a basal ganglia hemorrhage, which followed a transverse sinus thrombosis
that occurred five weeks after enrollment.
The thrombosis was treated with enoxaparin, heparin and warfarin, and
the patient died suddenly five days later.
The transverse sinus thrombosis was judged possibly related to study
drug and the basal ganglia hemorrhage was judged doubtfully related.
Serious Adverse Events
The rate of serious adverse events (SAEs) was 2.2% in the TTS group and 2.1% in the placebo
group. The most commonly reported SAEs
in the TTS group were application site reactions (1.3%) and nasopharyngitis and
headache (each 0.9%), and in the placebo group, application site reactions,
headache, migraine and back pain (each 0.6%).
Withdrawals
due to Adverse Events
Eight
percent of subjects in each group withdrew due to adverse events (AEs) in the
double blind phase. The most common AEs
associated with withdrawal were application site reactions (ASRs) in both
groups and hirsutism in the TTS group.
AEs in the overall categories of nervous system and psychiatric
disorders were also responsible for a number of withdrawals in each group, each
accounting for withdrawal of 1-2% of the enrollees. Nervous system disorders resulting in
withdrawals included such MedDRA terms as headache, dysphonia, dizziness and
transient ischemic attack, and occurred in 14 TTS and 8 placebo subjects. Psychiatric disorders that resulted in
withdrawal included such MedDRA terms as anxiety, agitation, aggression and
depression, and occurred in 12 TTS and 13 placebo subjects.
Common Adverse Events
Overall, AEs occurred in 76.1% of TTS subjects and 75.8% of
placebo subjects. Events occurring at
>2% frequency and with a numerically greater incidence in the TTS group are
listed in Table 18. Events that
occurred most commonly in the TTS group during the double blind phase were
acne, upper respiratory infections, hirsutism and headaches. The TTS subjects had a higher proportion of
overall AEs reported by the Applicant to be possibly or probably drug-related
(26.8% vs. 23.4%), primarily due to greater occurrence of androgenic AEs. AEs that were considered by the Applicant
prior to unblinding to be potentially drug-related and that occurred at >2%
frequency and with a numerically greater incidence in the TTS group are listed
in Table 19.
Table
18 Studies 068, 092, 133 & 134: Most Common Adverse Events (≥ 2%) During Double Blind Phase
|
Adverse
Event
|
Placebo
|
TTS
|
|
|
N
|
%
|
N
|
%
|
|
Total
N
|
703
|
|
696
|
|
|
N
with at least one AE
|
533
|
75.8
|
530
|
76.1
|
|
|
|
Acne NOS
|
46
|
6.5
|
61
|
8.8
|
|
URI NOS
|
51
|
7.3
|
57
|
8.2
|
|
Hirsutism
|
35
|
5.0
|
49
|
7.0
|
|
Headache
|
44
|
6.3
|
48
|
6.9
|
|
Influenza
|
20
|
2.8
|
20
|
2.9
|
|
UTI NOS
|
19
|
2.7
|
20
|
2.9
|
|
Alopecia
|
15
|
2.1
|
20
|
2.9
|
|
Gastrointestinal &
abdominal pains (HLT)
|
9
|
1.3
|
19
|
2.7
|
|
Cough
|
15
|
2.1
|
16
|
2.3
|
|
Migraine NOS
|
12
|
1.7
|
16
|
2.3
|
|
Gastroenteritis viral NOS
|
13
|
1.8
|
15
|
2.2
|
|
Flushing
|
13
|
1.8
|
15
|
2.2
|
|
Hypertension NOS
|
9
|
1.3
|
14
|
2.0
|
|
Influenza-like illness
|
8
|
1.1
|
14
|
2.0
|
Table
19 Studies 068, 092, 133 & 134: Adverse Events Considered Possibly or
Probably Drug-Related in Double Blind Phase
|
Adverse
Event
|
Placebo
|
TTS
|
|
|
N
|
%
|
N
|
%
|
|
Total
N
|
703
|
|
696
|
|
|
|
|
Acne NOS
|
41
|
5.8
|
55
|
7.9
|
|
Hirsutism
|
33
|
4.7
|
49
|
7.0
|
|
Alopecia
|
14
|
2.0
|
17
|
2.4
|
Among cardiovascular, thrombotic and cancer-related events
of interest, there were no MIs in either group during the double blind phase,
although one placebo subject reported coronary artery disease as an AE and two
TTS subjects reported angina as AEs.
There was a cerebral hemorrhage and transverse sinus thrombosis in a
placebo subject (the one death in the trial) and a transient ischemic attack
(TIA) in a single TTS subject. There was
a single DVT in a TTS subject, who had a past history of DVT and Factor V
Leiden. There was a single case of
breast cancer in the placebo group.
In addition to assessing AE reports of androgenic effects,
systematic ascertainment was made of several individual androgenic
effects. At baseline, and Weeks 12, 24,
36 and 52, assessments at the lip and chin for increased hair were made, with
scoring done according to the facial portion of the Lorenzo Pictorial Rating
Scale (rated from 0-4), and assessment of facial acne was assessed on a 0-3
scale developed by Palatsi et al.
Subjects were also asked at these visits about frequency of depilation. In addition, subjects were queried about voice
changes or changes in scalp hair at Weeks 4, 24 and 52.
Hirsutism, acne and alopecia were the primary manifestations
of androgenic effects noted in the trial subjects. Other events of concern include voice
deepening (dysphonia or hoarseness), clitoromegaly and potential psychiatric
effects (increased aggression, agitation or irritability).
The frequency of androgenic AEs during the double blind
phase was higher in the TTS group (17.7%) than the placebo group (14.4%),
primarily due to higher rates of acne and hirsutism (see Table 20). TTS subjects
were also more likely to experience multiple androgenic AEs and to withdraw due
to these AEs.
Table
20 Studies 068, 092, 133 & 134: Androgenic AEs in Double Blind Phase
A single TTS subject reported clitoromegaly during the
double blind phase; this was confirmed on physical examination, and resolved a
month following study discontinuation.
Her free testosterone level was 2.2 pg/ml (normal range 0.9 – 7.3
pg/ml).
Psychiatric AEs of interest as possible androgenic effects
were specified by the Applicant as agitation, aggression or irritability. Frequency of these events were assessed based
on these MedDRA terms, either from spontaneous subject reports or from AEs
detected by investigators or other site personnel, and they occurred in 2% of
subjects in each group. The rate of
aggression was also identical, 0.9%, in each group.
Acne
AEs relating to acne were reported by 9.1% of TTS subjects
and by 7.0% of placebo subjects in the double blind phase.
On the objective assessment of
acne using the Palatsi acne scale, the TTS subjects showed greater frequency of
increased acne scores, although the inter-group differences were not
statistically significant. At Week 24,
3.3% of TTS subjects experienced increases of one or more points on the
four-point Palatisi acne scale, as opposed to 2.4% of placebo subjects.
Alopecia
Alopecia was reported as an AE
in 3.4% of TTS subjects and 2.7% of placebo subjects, and withdrawal rates were
similar.
Hirsutism
Hirsutism was reported as an AE in 7.0% of TTS subjects
and 5.0% of placebo subjects.
On the objective assessment, the Lorenzo scale, the
rating of chin hirsutism increased from baseline in 6.1% of TTS subjects and
3.7% of placebo subjects by Week 24, and upper lip hirsutism increased in 6.6%
of TTS subjects and 5.6% of placebo subjects by Week 24. Facial depilation frequency increased in
13.2% of both TTS and placebo subjects by the end of the double blind phase.
Voice Deepening
Voice deepening (defined as dysphonia
or hoarseness) was reported as an adverse event in 2.3% of TTS subjects and
1.7% of placebo subjects in the double blind phase. Two TTS subjects withdrew due to this
AE. One of these subjects rated her
hoarseness severe, and it reportedly resolved two months after discontinuation
of testosterone.
5.3.1.3
Application Site Reactions
Data on application site reactions were pooled only over the
two phase 3 trials, as the severity criteria differed between the phase 2 and
phase 3 studies, and because the Study 068 subjects wore two patches
simultaneously to protect the blind.
Rates were similar between the phase 2 and phase 3 studies. Fewer than 5% of phase 2 subjects discontinued
participation due to application site reactions. Application site reactions occurring during
the double blind phase were slightly higher in the placebo group (34.1% vs.
30.4%). Two subjects in each group were
reported as possible cases of sensitization, but no confirmatory testing was
performed. Three of these four subjects
withdrew from the study.
Effects of possible interaction between testosterone and the
estrogen therapy also administered to subjects were evaluated by assessing the
occurrence of hot flushes and breast tenderness. The rate of hot flushes was numerically
slightly greater in the TTS group (2.7% vs. 2.4%), and slightly more TTS
subjects experienced severe hot flushes in the double blind phase (three vs.
one placebo subject).
In the phase 2 studies, breast pain and tenderness was
captured both by spontaneous adverse event reports and by directed questioning
about breast tenderness at baseline and post-treatment. In the phase 3 studies, only spontaneous
reports were used to count these events.
Over the four studies, 4.2% of
TTS subjects had breast pain AEs as compared to 4.8% of placebo subjects. Distributions of severity were similar
between the two groups.
The laboratory data were pooled separately for phase 2 and
for phase 3 studies, as different clinical labs were used to run the tests in
the two phases. Only data from the phase
3 studies are reported below; the results in the phase 2 studies were generally
consistent with those obtained in the phase 3 studies. Limits for markedly abnormal laboratory
values are found in Appendix 3.
Lipid
Profile
Changes from baseline in lipid profile during the double
blind phase were small and not likely to be of clinical significance (Table 21). The TTS group
had a smaller mean increase in HDL at Week 24 than did the placebo group (mean
change 0.4 vs. 1.6 mg/dl in placebo).
The frequency of markedly abnormal values was low, and similar between
groups (see Table 22).
Table
21 Studies 133 & 134: Changes in Lipid Profile in Double Blind
Phase
Table 22 Studies 133 & 134: Proportion of Subjects with Markedly
Abnormal Values on Lipid Profiles in Double Blind Phase
|
Laboratory
Test
|
Placebo
N=545
|
TTS
N=549
|
|
# abnl/
# with data
|
%
|
# abnl/
# with data
|
%
|
|
Total Cholesterol
|
1/479
|
0.21
|
1/488
|
0.20
|
|
HDL
|
0/479
|
0
|
0/488
|
0
|
|
LDL
|
7/479
|
1.46
|
5/488
|
1.02
|
|
Triglycerides
|
14/479
|
2.92
|
12/488
|
2.46
|
Hepatic Profile
Changes in hepatic function during the double blind phase
are displayed in Table
23. A
single placebo subject had a markedly abnormal AST (baseline of 28 U/L rose to
126 at Week 24). A single TTS subject
had a markedly abnormal ALT (baseline of 9 U/L rose to 191 at Week 24).
Table
23 Studies 133 & 134: Changes in Hepatic Function in Double Blind
Phase
Carbohydrate Metabolism
Changes in carbohydrate metabolism during the double blind
phase are displayed in Table
24, with the frequency of markedly abnormal
values in each group shown in Table
25.
Table
24 Studies 133 & 134: Changes in Carbohydrate Metabolism
Markers during Double Blind Phase
Table
25 Studies 133 & 134: Proportion of Subjects with Markedly
Abnormal Values on Carbohydrate Metabolism Markers in Double Blind Phase
|
Laboratory
Test
|
Placebo
N=545
|
TTS
N=549
|
|
# abnl/
# with data
|
%
|
# abnl/
# with data
|
%
|
|
Glucose
|
0/480
|
0
|
0/486
|
0
|
|
Hemoglobin
A1c
|
0/475
|
0
|