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


1          baCKGROUND

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.”

1.1        Definition of FSD

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]

1.1.1        Hypoactive Sexual Desire Disorder

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).   

1.2        FDA Guidance

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

1.3        Agreements with Applicant

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

 

2          Clinical development

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. 

2.1        Testosterone Therapy for HSDD

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. 

2.2        Applicant’s Early Clinical Development Program

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. 

2.3        Dose Selection

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. 

2.4        Instrument Development and Validation

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. 

2.5        Overview of Clinical Trials

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

 

 

*MICD = minimally important clinical difference or minimally meaningful clinical difference.

** N= 771 unique subjects using the TTS 300 mcg/day dose; does not include the 64 exit interview and 102 withdrawal subjects. 

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).

3          Clinical Trial Design

3.1        Description of Phase 2 Trial Protocols

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.

3.2        Description of Phase 3 Trial Protocols

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.  

3.3        Inclusion/Exclusion Criteria

3.3.1        Inclusion Criteria

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;

3.3.2        Exclusion Criteria

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:

·         In the Phase 2 studies T96006 and 1999068, per protocol, all the women had documented low serum testosterone levels [free T <3.5 pg/mL; normal range is 0.9-7.3]. This free T criterion was dropped in the Phase 3 studies because the Applicant’s Phase 2b experience indicated that almost no potential study subject had baseline T levels exceeding the level set.  Baseline serum testosterone parameters were obtained, however, as were testosterone levels at Weeks 12 and 24 during the 2 controlled Phase 3 trials.

3.4        Schedule of Assessments

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

 

 


3.5        Endpoints & Statistical Analysis

3.5.1        Primary Endpoint

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. 

3.5.2        Principal Secondary Endpoints

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.)

3.5.3        Primary Analysis

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.

4          Clinical Trial Outcomes

4.1        Enrollment

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%)

4.2        Demographic Data - Combined Trials

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

Division comment:

·         The population in this study reflects the age group who has undergone hysterectomy in the U.S., but African American women are dramatically underrepresented in the study populations.  Data from the MMWR Hysterectomy Surveillance – United States, 1994-1999 reported by Keshavarz H, et al, found that women aged 40-44 had the highest hysterectomy rate compared to other age groups – 52% of hysterectomies were performed in women <45 years of age.  Fifty-five percent of women in the U. S. who had a hysterectomy had a bilateral oophorectomy.  When age and race were examined together, the group with the highest rate of hysterectomy was African American women aged 40-44 years – 16.8 per 1,000, compared to 10.8 per 1000 in the same age group of white women.  

4.3        Discontinuation (withdrawal) Rates

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. 

4.4        Efficacy Outcomes

4.4.1        Baseline Findings

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. 

Division comment:

·         Data collected by the Applicant early in the development program in 2000 during the time of the initial 3 instrument validation studies showed on average 3-4 total satisfying sexual episodes (SSEs) per 4 weeks in women with HSDD [N= 347] in Europe, the U.S. and Canada compared with "normal" age-matched controls [N= 260] who reported 10-12+ SSEs per 4 weeks. The sexual desire score associated with HSDD was 30 ± 5 (0-100 range) and with normal controls was 60 ± 5. The personal distress score (0-100 range) was 55 ± 5 in women with HSDD and 5 ± 2 in age-matched controls.

·         It is of note that a PFSF sexual desire score of 21 corresponds, on average, to “seldom” having an interest in sexual activity, and that a PDS score of 65 corresponds, on average, to being “often” distressed about the lack of interest in sexual activity. 

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.

Division comment:

·         A significant percentage of subjects were using higher doses of estrogen.   Current guidelines recommend use of the lowest effective dose of estrogen.  It is unclear whether women in these studies were on the lowest effective dose of estrogen for them as individuals.

4.5        Primary Efficacy Outcome (total SSEs at Week 24)

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. 

Division comment:

·         The Division statistician found the analysis plan to be acceptable.

 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

* Source: E-Table 4, ISE.
a  The frequency of SSEs was based on data from the SAL from baseline and the last 4 recorded weeks.
b Mean change from baseline adjusted for age, estrogen therapy route, pooled centers, and baseline value.

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

Data for individual studies shown corresponds to the mean change from baseline (±) 1 standard error (SE).  Data for combined studies corresponds to mean change from baseline adjusted for study (±) 1 standard error.

** =p<0.01;  ***=p<0.001 based on analysis of covariance (ANCOVA) model for combined studies and Wilcoxon Rank-Sum (WRS) test for individual studies.

 

Division comment:

·         The crucial question is the clinical significance of the change with active treatment yielding, on average, one more satisfying sexual event per 4 weeks compared to placebo.

4.6        Principal Secondary Endpoints

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.

Division comment:

·         Experts in the field consider that both an increase in sexual desire and a decrease in personal distress are necessary components of a clinically meaningful HSDD treatment.

4.6.1        Change in Personal Distress 

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.

Division comment:

·         The Applicant reports that women without HSDD have a score of 5 ± 2 on this scale.

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

a  Range for distress score is 0-100.
b Mean change from baseline adjusted for age, estrogen therapy route, pooled centers, and baseline value.

 

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)

Data for individual studies shown corresponds to the mean change from baseline (±) 1 standard error.

Data for combined studies corresponds to mean change from baseline adjusted for study (±) 1 standard error.  ** = p<0.01;  *** = p<0.001 based on analysis of covariance (ANCOVA) model.

Division comment:

·         The difference in mean reduction in the distress scores in the TTS treated subjects compared to those in the placebo group correspond to less than an average change of one unit on the PDS questionnaire's response scale (range 1 to 6).

4.6.2        Change in Sexual Desire

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.

Division comment:

·         The Applicant reported that women without HSDD had a score of 60 ± 5 for this domain.

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

*Source: E-Table 5, ISE.

a  Range for sexual desire score is 0-100.
b Mean change from baseline adjusted for age, estrogen therapy route, pooled centers, and baseline value.

 

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)

Data for individual studies corresponds to mean change from baseline (±) 1 standard error (SE).

Data for combined studies corresponds to mean change from baseline adjusted for study (±) 1 standard error.   

* = p<0.05;  *** = p<0.001 based on analysis of covariance (ANCOVA) model.  LOCF= last observation carried forward.

 

Division comment:

·         The clinical significance of the increase with active treatment yielding, on average, an increase of only 5-6 points more than placebo on a scale of 100 is unknown.

4.7        Summary of Phase 3 Efficacy Findings

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.

 

4.8        Secondary Analyses of Primary and Principal Secondary Endpoints

4.8.1        Responder Analyses

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%)

The LOCF analysis at Week 24 was based on responses recorded on the last SAL evaluated.

The sample is the number of subjects with baseline and Week 24 (LOCF) responses.

A A responder is a patient with a change from baseline in their total SSEs of > 1 episode.

 

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%)

The LOCF analysis at Week 24 was based on responses recorded on the last PFSF evaluated.

The sample is the number of subjects with baseline and Week 24 (LOCF) responses.

A A responder is a patient with a change from baseline in their sexual desire score ³ 8.89.

 

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)

 n (%) = number and percentage of women in category; N = sample size

4.8.2        Onset of Treatment Effects:

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

4.9        Persistence of Treatment Effect

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 

 

Division comment:

·         The goal of the randomized discontinuation study was to assess the dependence of the apparent treatment effect upon continuation of active therapy.  In order to assess this meaningfully, the same efficacy assessments should be employed as were used in the efficacy studies.  Use of different assessment tools and endpoints by the Applicant makes interpretation of the results difficult.

4.10    Study CMK#US030993  (Minimally Important Clinical Differences)  

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

*Interview population (N= 132): change from baseline in given parameter at Week 24

Mean baseline values for all subjects in the Phase 3 trials were:  SSEs= 3.0; Distress score=65.1; Desire score = 21.4

 

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).

Division’s comment:

·         Small differences in outcomes between active and placebo treatment groups may be statistically significant yet clinically unimportant.  Making this distinction is particularly important, and often quite difficult, for outcomes based on health-related quality of life endpoints.  The design and interpretation of studies to identify minimally important clinical difference (MICDs) can be difficult and fraught with problems. Experts in the development, validation, and interpretation of instruments to determine MICDs may not agree with:

- 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.

4.11    Summary of Efficacy and Related Issues

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.

 

Division comment:

·         Although all these differences were statistically significant, it is unknown whether they are clinically meaningful.

 

 


5          Safety

5.1        Overview of Safety Concerns with Testosterone

In the aftermath of the Women’s Health Initiative (WHI) studies[1],[2] 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: 

The safety database for subjects using TTS was examined for evidence of these effects in women treated with testosterone and estrogen therapy. 

5.2        Overview of Safety Database

5.2.1        Studies Included

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. 

5.2.2        Demographics of Safety Population

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

Source:  E-Table 3, eff-sum.pdf, p 118-9

5.2.3        Safety Outcomes Evaluated

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. 

5.3        Findings from Clinical Trials

5.3.1        Safety Findings –Testosterone vs. Placebo 

5.3.1.1       Adverse Events

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

Note:  HLT = Higher Level MedDRA Term, subsuming subheadings; NOS = Not otherwise specified

Source:  Based on Table 7, safety-sum.pdf, pp 75-124  

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

Note:  HLT = Higher Level MedDRA Term, subsuming subheadings; NOS = Not otherwise specified

ASRs are excluded from this listing.

Source:  Based on Table 7, safety-sum.pdf, pp 75-124  

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. 

5.3.1.2       Androgenic Effects

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

Source:  S-Table 6, safety-sum.pdf, p 23

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.

5.3.1.4       Impact on Estrogen-Related Effects

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.

 

5.3.1.5       Laboratory Values

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

Source:  S-Table 14, safety-sum.pdf, p 46

 


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

Source:  Appendix 5.9, Table 4, 2001133.pdf, p 11154 and Appendix 5.9, Table 4, 2001134.pdf, p 10113

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

Source:  S-Table 16, safety-sum.pdf, p 50

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

Source:  S-Table 18, safety-sum.pdf, p 53

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