RANDOMIZED, PLACEBO-CONTROLLED, DOUBLE BLIND, CROSSOVER DESIGN PILOT TRIAL OF THE EFFICACY AND SAFETY OF ZESTRA™ FOR WOMEN IN WOMEN WITH, AND WITHOUT, FSAD.

D. Ferguson, C. Steidle, G. Singh, S. Alexander, K. Weihmiller, and M. Crosby, 2001. Test articles provided by QualiLife Pharmaceuticals, Inc.

Introduction: Zestra™ for Women is a topically applied, botanical feminine massage oil formulated to enhance female sexual pleasure, increase warmth, sensitivity, & sensation, & facilitate arousal when applied to the clitoris, labia, and vaginal opening. Zestra™ for Women is not a drug. This product is not intended to diagnose, treat, cure, or prevent any disease and has not been evaluated by the FDA. This pilot study was conducted to evaluate the efficacy and safety of Zestra™ for Women compared to a placebo oil in women with, and without, Female Sexual Arousal Disorder (FSAD) in conditions of home use in conjunction with sexual activities.

Methods:

Design: Zestra™ for Women was studied in 10 women with Female Sexual Arousal Disorder (FSAD) and 10 normal women in a double-blinded, placebo-controlled, 2-way crossover design. The placebo was matched to the active test article based on viscosity, fragrance, color, absorbency, and lubricity. At the screening visit, each subject was interviewed by a sex therapist, underwent a physical examination, and completed the Female Sexual Function Index (FSFI)© and the Female Sexual Distress Scale (FSDS)©. Women with FSDS scores greater than 60 were excluded from participation. Subjects were randomized to treatment paths, given five 1 ml doses of test article, and instructed in the use of the diary, the Female Sexual Encounter Profile (FSEP)©. Subjects were to return to the clinic for Visit 2 after completing 5 usages of the test article at home. At Visit 2, they completed the FSFI, the FSDS, two global assessment questions (GAQ)©, and the QualiLife Consumer Testing Survey (QCTS)©. They were then given five 1 ml doses of the cross-over test article and provided 5 more diaries. At the final visit, Visit 3, subjects again completed the FSFI, the FSDS, the GAQ, and the QCTS.

Inclusion/exclusion criteria: Subjects were diagnosed as "normal" or FSAD based on interview by the sex therapist. Subjects were postmenopausal, or using hormonal contraception for at least 3 months prior to study entry, or had had a documented tubal ligation at least 3 months prior to study entry, or their partner was vasectomized. FSAD subjects were required to have previously been fully functional, now have a score between 40 and 60 on the FSDS, and be willing to attempt sexual activities at least 3 times weekly. Normal subjects were required to have a FSDS score less than 40. Exclusion criteria included unresolved sexual trauma or abuse; primary anorgasmia, vaginismus, sexual pain disorder, or sexual aversion disorder; pregnancy or nursing; currently active moderate to severe vaginitis; use of neuroleptics or lithium, or bupropion within previous 3 months; and any condition which in the Investigator's opinion would endanger the subject, would interfere with the subject's ability to provide informed consent or to comply with study instructions, or which might confound the interpretation of the study results. Subjects were not excluded due to use of antidepressants, nutritional supplements, or hormonal replacement therapy.

Endpoints: Safety was assessed by monitoring adverse events (AEs). The primary efficacy variable was the number of successes (satisfaction with sexual arousal as indicated by YES responses to diary question 3) divided by the number of attempts (FSEP Q3). The secondary efficacy parameters were the responses to the global assessment questions, the remaining diary questions, the Female Sexual Function Index, and the Female Sexual Distress Scale. Paired-t analyses were employed to assess treatment effects for each subject compared to placebo effects. Sequence and carryover effects were assessed by group mean comparisons of the primary efficacy variable. No attempt was made to statistically compare responsiveness of the normal versus the FSAD subjects.

Results:

Safety: All 20 subjects completed the study. Three subjects reported single incidences of mild genital burning sensations of 5-30 minute duration while using Zestra™. One subject reported several incidences of vaginal irritation associated with coitus while using placebo. She was subsequently diagnosed and treated for a yeast infection. Two AEs reported while on placebo treatment were considered unrelated to the test article: fatigue associated with hypothyroidism, and a sinus infection.

Efficacy: There was no statistical evidence of carryover effects. Table 1: shows the mean changes in responses for the FSEP, FSFI, FSDS, and the GAQ for both subject groups. The primary efficacy variable, FSEP Q3, which assesses satisfaction with level of arousal, has a range of 0 to 1. Normal subjects had a mean score of 0.730 + 0.297 while on placebo and a mean score of 0.950 + 0.158 while on Zestra™. The mean improvement in the FSEP Q3 score was 0.220 + 0.277, which was statistically significant (P = 0.0333) by paired-t analysis. FSAD subjects had a mean score of 0.287 + 0.337 while on placebo and a mean score of 0.855 + 0.315 while on Zestra™. Their mean improvement in the FSEP Q3 score was 0.568 + 0.360, which was statistically significant (P = 0.00074) by paired-t analysis.

Secondary efficacy variables included the FSEP questions 2, 4, 5, and 6, as well as a FSEP total score (sum of Q2-Q6). FSEP Q2 assesses level of desire and has a range of 0 to 3. Highly significant improvements in this diary based desire variable were seen in both normal subjects (P = 0.00041) and FSAD subjects (P = 0.00011). FSEP Q4 asks if the subject had lubrication sufficient to allow comfortable intercourse (even if intercourse did not actually occur). Neither normal nor FSAD subjects showed significant changes in FSEP Q4. The FSAD subjects showed a statistically significant (P = 0.013) increased frequency of orgasms (FSEP Q5), but the normal subjects failed to reach significance (P = 0.053). FSEP question 6 assesses level of arousal and has a range of 0 to 3. Normal subjects showed a significant (P = 0.0063) increase in level of arousal as did the FSAD subjects (P = 0.00091). FSEP Total (range = 0-9) was significantly increased in normal subjects (P = 0.0027) and FSAD subjects (P = 0.00012).

The Female Sexual Function Index (FSFI)© provides six factored domain scores with a maximum score of 6 for each domain. Additionally, a total score (maximum = 36) is calculated. Higher scores indicate a more "healthful" condition. The domains are desire, arousal, lubrication, orgasm, satisfaction, and pain. Zestra™ produced significant improvements in the arousal domain in normal subjects and in the arousal and orgasm domains and in the FSFI total score in the FSAD subjects. There were no deleterious changes in either subject group.

The Female Sexual Distress Scale (FSDS)© is a 20 question instrument with a range of 0 to 80. A lower score indicates a less distressed situation. Although Zestra™ produced decreases in both groups, no change was significant.

The Global Assessment Questions (GAQ)© were these: GAQ 1: While using the study medication, did you feel that your level of sexual arousal (excitement) improved? [0=Not at all; 1=A little, but barely noticeable; 2=Somewhat; 3=Quite; 4=Greatly]. GAQ 2: While using the study medication, did you feel that your sexual pleasure was enhanced? [0=Not at all; 1=A little, but barely noticeable; 2=Somewhat; 3=Quite; 4=Greatly]. While on placebo, both subject groups had mean scores in the 0.4 to 0.6 range. Zestra™ produced strong and very significant improvements in the scores for each question.

The QualiLife Consumer Testing Survey (QCTS)© consists of twelve questions intended to assess users' responses and attitudes regarding the product. Questions 1, 6, 7, 8, 9, 10, and 12 are quantitative. Question 1 assesses genital sensation. Question 6 assesses pleasure associated with sexual activities. Question 7 assesses lubrication. Question 8 addresses enhancement of ability to have orgasms. Question 9 addresses enhancement of sexual experiences. Question 10 addresses willingness to purchase the product. Question 12 asks subjects how much they would pay for the product. Table 2: shows the group mean results of these questions for both subject groups with asterisks indicating significance from paired-t analyses. Both normal and FSAD subjects showed significant improvements in sensation, pleasure, ability to have orgasms, enhancement of sexual experiences, willingness to purchase the product, and the price they would pay for the product.

Discussion: This study is a landmark in testing nondevice products in women with FSAD. This is the first study to show positive results in at-home conditions. Other studies have only shown positive results in in-clinic models with visual sexual stimulation. It should also be noted that Zestra™ produced beneficial effects in normal women also. This is believed to be the first study reported to use a parallel group of normal women. The primary efficacy variable FSEP Q3 directly addresses the critical question established in FDA guidelines for drug products pursuing an indication in Female Sexual Arousal Disorder. This nondrug pruduct produced significant improvements in this parameter in both normal and FSAD women. This result was supported by 14 significant improvements out of 21 secondary efficacy variables in FSAD women. Similarly, normal women showed 12 out of 21 significant improvements. No efficacy variable showed a deleterious change in either subject group.

It is interesting to note that the diary (FSEP©), GAQ©, and the QCTS© results correlated well with each other, but the FSFI© and FSDS© results appeared to only be weakly supportive, particularly with the normal subjects. Both of the latter instruments are non-product specific recall questionnaires. Within the design of this study, each subject had only five exposures to placebo and five exposures to Zestra™ over treatment periods of 2-3 weeks. This may have been insufficient time to allow solidification of new attitudes. This raises the study design issue of defining adequate treatment period durations and numbers of exposures. In effect, the half-life of an attitude is a critical concern. Although data were not presented here, there was an indication of the Hawthorne effect when the FSDS data were graphed against time. This would suggest that a long placebo-controlled run-in period (1 month or greater) would be desirable in future studies to establish a stable baseline.

There has been reluctance to include consumer testing questions in clinical trials based on notions of the impurity of "commercial issues." Yet, the ultimate satisfaction of the end users of products under development should be a vital concern of those who are responsible for these trials. The consumer testing questions used in this study supported the other efficacy results and specifically addressed how much the subject valued the treatment. In some ways, this is the inverse of a bother index. The success of a product will depend on the users' willingness to purchase and use the product. The subjects in this study indicated that they valued this product.

Conclusions: Zestra™ for Women is safe under these conditions of use. Zestra™ for Women improves level of desire, satisfaction with level of sexual arousal, level of sexual arousal, genital sensation, sexual pleasure, ability to have orgasms, and enhancement of sexual experiences in normal and FSAD women. Both normal and FSAD women are willing to purchase Zestra™ for Women at a significant price.