`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The New England Journal of Medicine
`
`A CONTROLLED TRIAL OF NONOXYNOL 9 FILM TO REDUCE MALE-TO-FEMALE
`TRANSMISSION OF SEXUALLY TRANSMITTED DISEASES
`
`R
`ONALD
`
` E. R
`ODDY
`
`, B.A., U
` A. R
`.D., K
`, P
` Z
`, M.P.H., L
`BALD
`YAN
`ELLEY
`H
`EKENG
`ÉOPOLD
`S
` S. W
`, P
`.D.,
` E
` L. W
`, D
`.P.H.
`EIR
`HARON
`H
`AND
`MELITA
`ONG
`R
`
` T
`AMOUFÉ
`
`, M.S
`C
`
`.E.,
`
`A
`BSTRACT
`Background
`Nonoxynol 9 is a proved spermicide,
`but whether it is also a microbicide is uncertain. A
`truly effective vaginal microbicide would reduce the
`susceptibility of women to sexually transmitted dis-
`eases, including infection with the human immuno-
`deficiency virus (HIV).
`Methods
`We enrolled 1292 HIV-negative female
`sex workers in Cameroon in a double-blind, placebo-
`controlled study in which the participants were ran-
`domly assigned to use either a film containing 70
`mg of nonoxynol 9 or a placebo film, inserted into
`the vagina before intercourse. All of the women
`were provided with latex condoms and were in-
`structed to have their male sexual partners use them.
`At monthly follow-up visits, we examined the wom-
`en with a colposcope for genital lesions, tested en-
`docervical specimens for gonorrhea and chlamydia
`infection with DNA probes, tested for HIV infection,
`and treated the women for curable sexually trans-
`mitted diseases.
`Results
`The rates of HIV infection (cases per 100
`woman-years) were 6.7 in the nonoxynol 9 group
`and 6.6 in the placebo group (rate ratio, 1.0; 95 per-
`cent confidence interval, 0.7 to 1.5). The rates of
`genital lesions were 42.2 cases per 100 woman-
`years in the nonoxynol 9 group and 33.5 in the pla-
`cebo group (rate ratio, 1.3; 95 percent confidence in-
`terval, 1.0 to 1.6). The rates of gonorrhea were 33.3
`and 31.1 cases per 100 woman-years in the nonox-
`ynol 9 and placebo groups, respectively (rate ratio,
`1.1; 95 percent confidence interval, 0.8 to 1.4). The
`corresponding rates of chlamydia infection in the
`nonoxynol 9 group and the placebo group were 20.6
`and 22.2 cases per 100 woman-years (rate ratio, 0.9;
`95 percent confidence interval, 0.7 to 1.3). The wom-
`en reported that condoms were used during 90 per-
`cent of sexual acts.
`Conclusions
`The use of a nonoxynol 9 vaginal
`film did not reduce the rate of new HIV, gonorrhea,
`or chlamydia infection in this group of sex workers
`who used condoms and received treatment for sex-
`ually transmitted diseases. (N Engl J Med 1998;339:
`504-10.)
`©1998, Massachusetts Medical Society.
`
`504
`
`·
`
`August 20, 19 98
`
`N
`
`ONOXYNOL 9 is a nonionic detergent
`that has been used as a spermicide since
`the 1950s. By disrupting the membranes
`of epithelial cells, bacteria, and viruses,
`nonoxynol 9 inactivates many sexually transmitted
`pathogens in vitro, including
`Neisseria gonorrhoe-
`
`
`ae,
`Chlamydia trachomatis,
`Haemophilus ducreyi,
`1,2
`3-5
`6
`
` Trichomonas vaginalis,
` and the
`Treponema pallidum,
`1
`2
`herpes simplex virus.
` Nonoxynol 9 appears to be
`5,7,8
`moderately effective in vivo as prophylaxis against
`cervical infection by
`and
`N. gonorrhoeae
`C. tracho-
` and vaginal infection by
` and
`T. vaginalis
`matis
`9-12
` pro-
`the bacteria associated with bacterial vaginosis,
`13
`viding a 25 percent reduction in the rate of infection.
`Evidence from in vitro studies
` and animal
`14-17
`models
` shows that nonoxynol 9 can inactivate
`18,19
`the human immunodeficiency virus (HIV), but three
`clinical studies
` have had conflicting results. A
`12,20,21
`randomized, controlled trial of the 1000-mg nonox-
`ynol 9 vaginal sponge, conducted among 138 female
`sex workers in Kenya, was stopped early because of
`an increase in HIV infection among the users of the
`sponge (rate ratio, 1.6; 95 percent confidence inter-
`val, 0.8 to 2.8).
` This same study reported an in-
`12
`crease in genital lesions and a decrease in cervical
`gonorrhea. A cohort study conducted among 273
`female sex workers in Cameroon reported a lower
`rate of HIV infection among women who consis-
`tently used suppositories containing 100 mg of no-
`noxynol 9 than among those who used the suppos-
`itories less consistently (rate ratio, 0.1; 95 percent
`confidence interval, 0.1 to 0.6).
` A cohort study
`20
`conducted among 110 couples in Zambia in which
`only the man was HIV-positive reported a crude rate
`ratio for HIV transmission of 0.5 (95 percent confi-
`dence interval, 0.1 to 3.8) among women who re-
`ported 100 percent use of nonoxynol 9 as compared
`with those who reported less than perfect use.
`21
`We conducted a randomized, controlled trial to
`determine the effect of a film containing 70 mg of
`nonoxynol 9, inserted vaginally before intercourse,
`on the rate of sexually transmitted diseases, includ-
`ing HIV type 1, among women. This study was
`performed in the context of the current recommen-
`
`From the Epidemiology Unit (R.E.R., K.A.R., S.S.W.) and the Biosta-
`tistics Division (E.L.W.), Family Health International, Durham, N.C.; and
`the Ministry of Public Health, Yaoundé, Cameroon (L.Z., U.T.). Address
`reprint requests to Mr. Roddy at Family Health International, P.O. Box
`13950, Durham, NC 27709.
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on October 7, 2016. For personal use only. No other uses without permission.
`
` Copyright © 1998 Massachusetts Medical Society. All rights reserved.
`
`Par Pharm., Inc., et al.
`Exhibit 1010
`Page 001
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`NONOXYNOL 9 FILM TO REDUCE MALE-TO-FEMALE TRANSMISSION OF SEXUALLY TRANSMIT TED DISEASES
`
`dations for prophylaxis against HIV infection: pro-
`motion of condom use by men and treatment of
`curable sexually transmitted diseases.
`
`METHODS
`
`Study Participants
`All participants were HIV-seronegative female sex workers re-
`siding in Yaoundé or Douala, Cameroon, who averaged at least
`four sexual partners per month; were between the ages of 18 and
`45 years; were not known to be allergic to latex or nonoxynol 9;
`were not pregnant or desiring to become pregnant in the next year;
`and were willing to learn their HIV-test results. We asked each
`woman to return monthly for follow-up visits for at least one year.
`
`Study Size
`We anticipated an incidence of HIV of 10 cases per 100 woman-
`years in the placebo group after the promotion of condom use,
` We
`on the basis of the previous cohort study in Cameroon.
`20
`estimated that 1000 women would need to be enrolled, given our
`assumptions of a rate ratio of 0.5 for HIV, 90 percent power to
`detect a 50 percent reduction in the rate of HIV infection, an alpha
`level of 0.05, a 20 percent loss to follow-up per year, a period of
`one year to recruit the cohort, and a period of at least one year
`of follow-up. For the study to have 90 percent power, 88 sero-
`conversions would have to occur.
`
`Study Procedures
`Study recruiters invited potential participants to attend a ses-
`sion at the study clinic, during which the staff described the study
`requirements, conducted the HIV-testing consent process, gave
`pretest counseling, tested for HIV infection, and asked interested
`women to return in one month for study enrollment. At the re-
`turn visit, each woman was given the results of her HIV test and
`post-test counseling. The HIV-negative women who consented
`to participate in the study proceeded to the base-line phase. The
`protocol and consent process were approved by the national eth-
`ics committee, the University of Yaoundé School of Medicine
`board in Cameroon, and an institutional review board at Family
`Health International; we obtained written informed consent from
`all the women for the initial determination of HIV serostatus and
`again one month later at enrollment.
`
`Randomization
`Family Health International produced randomization schedules,
`stratified according to clinic, using a computerized random-num-
`ber generator to select permuted blocks of eight. The treatment-
`group assignments were concealed in sequentially numbered,
`sealed opaque envelopes. The envelopes were opened only after
`enrollment. The clerk at each clinic gave the assignment envelopes
`to the interviewer, who made the assignments. This method of
`randomization prevents bias in randomized, controlled trials.
`22
`
`Blinding and Study Products
`The study was double-blinded — that is, neither the women
`nor the study staff, including the biostatisticians from Family
`Health International, knew which group was using the nonox-
`ynol 9 film. The nonoxynol 9 film contained 28 percent nonox-
`ynol 9 (70 mg), glycerin, and polyvinyl alcohol. The placebo film
`contained glycerin, polyvinyl alcohol, and less than 2 percent
`polysorbate 60. The two films were identical in appearance, pack-
`aging, and labeling.
`We chose film as the vehicle for nonoxynol 9 because it has
`characteristics that are likely to make it acceptable for widespread
`use — i.e., it is small (5 cm by 5 cm and paper thin), requires no
`applicator, is easy to use, dissolves in two to five minutes, and is
`not messy or affected by heat. The nonoxynol 9 film has been
`used as a spermicidal product for more than 15 years. We tested
`
`both films for in vitro inactivation of HIV. The nonoxynol 9 film
`inactivated HIV at a dilution of 0.035 percent but did not inac-
`tivate all the virus at 0.0035 percent. We do not know the con-
`centration of nonoxynol 9 achieved in vaginal fluids when film is
`used during coitus; however, one study has found a concentration
` The placebo
`of 7 to 11 percent in vaginal fluid after application.
`23
`film had no cell toxicity and did not inactivate HIV.
`The condoms provided were made of latex, were not lubricated
`with spermicide, and were 52 mm wide and 180 mm long. We
`urged all the women to use a film and have their male partners
`use a condom with each coital act. If a condom could not be
`used, the women were instructed to use the film alone.
`
`Data Collection
`We collected information on demographic characteristics and
`base-line sexual behavior during the screening visit to the clinic.
`Information needed to assess the randomization process and po-
`tential confounders was collected one month later when the
`women were enrolled. This information included data on the
`women’s history of sexually transmitted diseases, the frequency of
`intercourse according to type (oral, anal, or vaginal), condom and
`film use during vaginal intercourse, antibiotic use, method of
`contraception, blood transfusions, receipt of injections, and use
`of other vaginal agents (e.g., douches).
`Questions about the women’s sexual networks were designed
`to obtain information about types of sexual partners, such as new
`clients, regular clients, and nonclients, and about the use of con-
`doms and nonoxynol 9 with these various types of partners. To
`enhance recall, the women were interviewed monthly. Pictorial
`coital logs recorded information on each episode of vaginal inter-
`course, including the type of sexual partner (client or nonclient),
`whether a condom or a film was used (or both), and whether the
`condom broke. An interviewer tallied the coital log monthly. The
`logs served as a counseling tool for condom and film use and in-
`dicated whether the use of condoms and film was similar in the
`two study groups. The logs were not reliable enough to be used
`to assess compliance with recommendations for the use of film
`and condoms.
`We conducted an examination for genital ulcers, signs of genital
`irritation, and infections at the time of enrollment and at each
`monthly follow-up visit. We used colposcopes to examine the vulva,
`vagina, and cervix at each visit as a means of locating micro-
`ulcerations. We focused on the areas of the vagina that were ex-
`posed to the highest concentrations of nonoxynol 9. We palpated
`the inguinal lymph nodes, inspected the vulva and perineum for
`lesions, and inspected the introitus, vagina, and cervix. We placed
`a swab from the vaginal pool in a test tube with a few drops of
`normal saline for preparation of a wet mount (saline and potassi-
`um hydroxide). We took a specimen from the endocervix for the
`gonorrhea and chlamydia DNA-probe tests and performed a
`bimanual pelvic examination.
`The PACE 2 assay (Gen-Probe, San Diego, Calif.) was used to
`
`
`
`test for N. gonorrhoeae and C. trachomatis
` (sensitivity, 92 percent;
`specificity, 98 percent, as compared with culture for both organ-
`isms) and provided the information required for a diagnosis of
`cervical infection. A supplemental test to detect nonspecific signal
`was used to confirm positive results. The manufacturer of the
`PACE assay states that spermicide does not interfere with the
`assay.
`We determined HIV serologic status by the sequential method
`(in which positive status requires two positive enzyme immunoas-
`says followed by positive Western blot analysis).
`
`Outcome Measures
`The primary objectives of this clinical trial were to determine
`the effect of the nonoxynol 9 vaginal film on the rate of HIV
`infection, to measure its effect on the rate of genital ulcers, and
`to measure its effect on the rate of cervical gonorrhea and chla-
`mydia infection. The measures used for determining the occur-
`rence of infection were the crude incidence-density rates and the
`
`Volume 339 Number 8
`
`·
`
`505
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on October 7, 2016. For personal use only. No other uses without permission.
`
` Copyright © 1998 Massachusetts Medical Society. All rights reserved.
`
`Par Pharm., Inc., et al.
`Exhibit 1010
`Page 002
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The New England Journal of Medicine
`
`T
`
` A
`
` U
` C
`-L
` B
`. S
` 1
`SSESS
`TO
`SED
`HARACTERISTICS
`INE
`ASE
`ELECTED
`ABLE
`R
`
`
` P
`-A
` P
`.*
`OPULATION
`ANDOMIZATION
`IN
`THE
`RIMARY
`NALYSIS
`
`
`
` 9
`
`N
`ONOXYNOL
`G
`ROUP
`(N=595)
`
`26.0±5.6
`99
`1.4±1.4
`
`86
`
`58
`
`27
`47
`10
`
`4.5±4.1
`49
`15
`13
`11
`
`
`
`P
`LACEBO
`G
`ROUP
`(N=575)
`
`25.5±5.7
`99
`1.4±1.5
`
`87
`
`58
`
`25
`43
`8
`
`3.7±3.5
`48
`15
`10
`12
`
`C
`HARACTERISTIC
`
`Age (yr)
`Able to read (%)
`No. of living children
`Contraceptive method (%)
`None
`Hormonal
`Other
`Use of douching (%)
`Use of another vaginal substance (%)
`Sexually transmitted disease in past
`3 mo (%)
`Years as sex worker
`Use of condom with last client (%)
`Vulvar ulcers present (%)
`Current gonorrhea infection (%)
`Current chlamydia infection (%)
`
`*Plus–minus values are means ±SD.
`
`Characteristics of the Study Participants at Base Line
`Base-line characteristics were similar in the two
`groups (Table 1). Other variables that were similar in
`the two groups included marital status (95 percent
`were unmarried in the nonoxynol 9 group, and 97
`percent in the placebo group), whether the woman
`was living with a man (2 percent and 1 percent), use
`of medicine in the previous 30 days (12 percent and
`11 percent), whether the woman ever practiced oral
`sex (24 and 27 percent) or anal sex (16 percent and
`17 percent), whether the woman’s male partners
`used a condom, and the numbers and types of sexual
`partners the woman had.
`The prevalence of sexually transmitted diseases at
`base line was similar in the nonoxynol 9 and placebo
`groups, and the percentage of women with genital
`ulcers at the time of physical examination in the two
`groups was similar. Eight percent of the women in
`the placebo group and 10 percent of those in the
`nonoxynol 9 group reported that they had contracted
`a sexually transmitted disease in the previous three
`months. No evidence suggests that the women ex-
`cluded from the primary-analysis population or the
`women who withdrew from the study early were sig-
`nificantly different from those included in the HIV
`primary-analysis population.
`
`Disposition of Study Participants
`There were no differences according to treatment
`group in the number of women who completed fol-
`low-up or withdrew from the study. Withdrawal
`curves for the two treatment groups were similar
`(P=0.39), with about 73 percent of each group
`
`Kaplan–Meier estimates of the cumulative probability of the de-
`tection of HIV and other sexually transmitted diseases. All meas-
`ures of effectiveness considered the time to the first evidence of
`infection.
`
`Safety
`The main issues of safety associated with the use of nonoxynol 9
`are whether it increases the risk of HIV infection and, secondari-
`ly, whether it increases the incidence of breaks in the genital ep-
`ithelium. The measures for determining the incidence of breaks
`in the genital epithelium were the crude incidence-density rates
`and the cumulative probability of lesions on the vulva, vagina,
`cervix, or any of the three sites.
`
`Statistical Analysis
`We used prevalence ratios to compare the base-line character-
`istics of the two groups. We used the log-rank statistic to test dif-
`ferences between the groups in Kaplan–Meier estimates of survival
`for the variables of time to a first event and study discontinuation.
`We calculated rate ratios using Cox proportional-hazards regres-
`sion models, with the clinic site as a covariate. We performed all
`analyses on an intention-to-treat basis.
`The population included in the primary analysis with respect
`to HIV consisted of all the HIV-negative women enrolled in the
`study who were randomly assigned to a treatment group and who
`had at least one additional HIV test. To be included in the gon-
`orrhea, chlamydia, or genital-lesion analysis, a woman had to have
`been in the population included in the HIV primary analysis, not
`to have had the disease being analyzed at the time of her initial
`physical examination, and to have had a follow-up examination.
`
`Interim Analysis
`One interim analysis was conducted, and the results were pre-
`sented to an independent data and safety monitoring board
`organized by the National Institute of Allergy and Infectious Dis-
`eases after one third of the total expected events had occurred. A
`two-sided log-rank test gave a critical value of 1.76 with a P value
` spending function was used to deter-
`of 0.54. The Lan–DeMets
`24
`mine that 0.004 of the type I error of 0.05 was spent on the in-
`terim analysis. The board recommended that the study continue.
`
`RESULTS
`Randomization began in March 1994, and the
`last follow-up visits were conducted in December
`1996. Of the 2290 women initially tested for HIV
`infection and interviewed, 1317 enrolled in the trial
`and received nonoxynol 9 or placebo film. Of the
`women not enrolled, 40 percent were HIV-positive,
`51 percent did not return after screening, and 9 per-
`cent were excluded for other reasons. Among the
`randomized women, 25 were not clearly HIV-nega-
`tive at enrollment, including 8 who were seropositive
`at screening, 15 who had seroconversion in the
`month between screening and enrollment, 1 who
`was not screened but was seropositive at enrollment,
`and 1 who was never tested. Of the 1292 women el-
`igible for the study, 69 in the placebo group and 53
`in the nonoxynol 9 group never returned for a follow-
`up HIV test. The remaining 1170 women (575 in the
`placebo group and 595 in the nonoxynol 9 group),
`who were HIV-negative at screening and enrollment
`and had at least one HIV test after enrollment, con-
`stituted the population for the primary analysis with
`respect to HIV.
`
`506
`
`·
`
`August 20, 19 98
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on October 7, 2016. For personal use only. No other uses without permission.
`
` Copyright © 1998 Massachusetts Medical Society. All rights reserved.
`
`Par Pharm., Inc., et al.
`Exhibit 1010
`Page 003
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`NONOXYNOL 9 FILM TO REDUCE MALE-TO-FEMALE TRANSMISSION OF SEXUALLY TRANSMIT TED DISEASES
`
`continuing in the study at 1 year and with a mean
`follow-up period of approximately 14 months. The
`number of women who withdrew from the study
`and the reasons for withdrawal from the study were
`similar in the two treatment groups (Fig. 1). There
`were three deaths, which were not related to study
`participation — one in the placebo group and two
`in the nonoxynol 9 group.
`
`Prospectively Measured Potential Confounding Factors
`The women in the two groups were involved in
`about the same total number of coital acts during
`the course of the study (Table 2). Condom use was
`reported for 90 percent of vaginal sexual acts and
`was slightly less common in the nonoxynol 9 group
`than in the placebo group. Condom and film use
`varied according to type of sexual partner. Film use
`without a condom was more likely to occur with
`nonclients (16 percent) than with clients (3 percent).
`The use of neither condoms nor film was more likely
`to occur with nonclients (6 percent) than with cli-
`ents (1 percent).
`
`women in the placebo group reported ever having
`had oral sex, as compared with 10 percent of the
`women in the nonoxynol 9 group (one seroconver-
`sion was detected in each group among the women
`who had had oral sex). Six percent of the women in
`the placebo group and 5 percent of those in the
`nonoxynol 9 group reported ever having had anal sex
`(two seroconversions were detected in each group
`among these women). The number of seroconver-
`sions among the women reporting nonvaginal sex
`was small, as compared with the total number of
`seroconversions (6 of 94).
`
`Effect on HIV, Gonorrhea, and Chlamydia
`There were a total of 94 HIV seroconversions —
`48 in the nonoxynol 9 group and 46 in the placebo
`group. The event rates in the two groups were almost
`identical (Table 3). The curves for HIV seroconver-
`sion for the two groups showed no divergence
`(P=0.85). Similar results were noted for gonorrhea
`and chlamydia, with virtually identical event rates in
`the two groups.
`
`Nonvaginal Sexual Acts
`The prevalence of oral and anal sex was similar in
`the two treatment groups. Eleven percent of the
`
`Effect on Genital Lesions
`The women in the nonoxynol 9 group were more
`likely to have genital lesions than those in the place-
`
`1292 were eligibleD
`for analysis
`
`644 receivedD
`placebo
`
`648 receivedD
`nonoxynol 9
`
`575 had at leastD
`1 follow-up visitD
`69 had noD
`follow-up visits
`
`1170 wereD
`included inD
`primary-analysisD
`population
`
`595 had at leastD
`1 follow-up visitD
`53 had noD
`follow-up visits
`
`112 withdrew afterD
`mm<12 mo:D
`
`m01 diedD
`m33 withdrew forD
`mm personal reasonsD
`m03 became pregnantD
`m60 were lost toD
`mm follow-upD
`m02 withdrew forD
`mm other reasonsD
`m13 withdrew forD
`mm unknown reasons
`
`117 withdrew afterD
`mm<12 mo:D
`m02 diedD
`m35 withdrew forD
`mm personal reasonsD
`m02 became pregnantD
`m59 were lost toD
`m mfollow-upD
`m03 withdrew forD
`m mother reasonsD
`m16 withdrew forD
`m munknown reasons
`
`463 completedD
`study
`
`941 completedD
`study
`
`478 completedD
`study
`
`Figure 1.
` Progress of Women through the Study and Reasons for Discontinuation.
`
`Volume 339 Number 8
`
`·
`
`507
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on October 7, 2016. For personal use only. No other uses without permission.
`
` Copyright © 1998 Massachusetts Medical Society. All rights reserved.
`
`Par Pharm., Inc., et al.
`Exhibit 1010
`Page 004
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The New England Journal of Medicine
`
`T
`
`ABLE
`
` S
` V
`
` F
`
` C
`
` U
`R
` 2.
`EXUAL
`AGINAL
`FOR
`ILMS
`AND
`ONDOMS
`OF
`SE
`EPORTED
`
` S
`, A
`
` T
`
` S
` P
`.
`YPE
`OF
`CCORDING
`TUDY
`DURING
`THE
`TO
`EXUAL
`ARTNER
`
` A
`
`CTS
`
`
`
`V
`ARIABLE
`
`P
`LACEBO
`CLIENT
`
` G
`ROUP
`
`NONCLIENT
`
`NONOXYNOL 9 GROUP
`CLIENT
`NONCLIENT
`
`number (percent)
`
`Use of film only
`Use of condom only
`Use of film and condom
`Use of neither film nor condom
`Total no. of coital acts
`
`3,465 (4)
`11,530 (12)
`77,830 (83)
`1,267 (1)
`94,092
`
`9,270 (18)
`6,891 (13)
`33,442 (63)
`3,247 (6)
`52,850
`
`2,792 (3)
`9,967 (10)
`83,146 (86)
`956 (1)
`96,861
`
`7,446 (15)
`5,808 (11)
`35,305 (69)
`2,576 (5)
`51,135
`
`TABLE 3. RATES OF HIV, GONORRHEA, AND CHLAMYDIA
`INFECTION IN THE PLACEBO AND NONOXYNOL 9 GROUPS.
`
`INFECTION AND
`TREATMENT
`GROUP
`
`HIV
`Placebo
`Nonoxynol 9
`Gonorrhea
`Placebo
`Nonoxynol 9
`Chlamydia
`Placebo
`Nonoxynol 9
`
`NO. OF
`WOMEN
`
`WOMAN-
`YEARS
`
`NO. OF
`EVENTS
`
`EVENT
`RATE*
`
`RATE RATIO
`(95% CI)†
`
`575
`595
`
`435
`441
`
`420
`451
`
`698
`720
`
`357
`342
`
`365
`384
`
`46
`48
`
`111
`114
`
`81
`79
`
`6.6
`6.7
`
`31.1
`33.3
`
`22.2
`20.6
`
`1.0 (0.7–1.5)
`
`1.1 (0.8–1.4)
`
`0.9 (0.7–1.3)
`
`*The event rate is the rate per 100 woman-years.
`†The placebo group served as the reference category. CI denotes confi-
`dence interval.
`
`bo group, although this difference was not significant
`(Table 4). Most lesions were on the vulva and in-
`cluded excoriations, fissures, and ulcers. Genital le-
`sions did not predict HIV seroconversion in this
`study. The HIV-infection rate per 100 woman-years
`in the placebo group was 5.9 among those with
`lesions and 5.0 among those without lesions. The
`HIV-infection rate for women in the nonoxynol 9
`group was 5.0 among those with lesions and 5.3
`among those without lesions.
`
`Blinding
`We asked 126 staff members their opinions of
`which film was the placebo. Eighteen percent thought
`film A (the placebo) was the placebo, 13 percent
`thought film B (nonoxynol 9) was the placebo, and
`69 percent had no opinion about which film was the
`placebo. Of the 68 peer educators (the staff mem-
`bers most likely to reflect the opinion of the partic-
`ipants), 16 percent thought film A was the placebo,
`13 percent thought film B was the placebo, and 71
`percent had no opinion.
`
`508
`
`·
`
`August 20, 19 98
`
`DISCUSSION
`Nonoxynol 9 film did not give the women in this
`study any additional protection against infection with
`HIV, gonorrhea, or chlamydia beyond that provided
`by condoms and treatment for sexually transmitted
`diseases. Our instructions to the women were that
`the vaginal film should be used in addition to con-
`doms for greater protection against sexually trans-
`mitted diseases; if a condom could not be used, the
`film should be used alone.
`25
`Our results with respect to HIV infection are con-
`sistent with the findings of the only other random-
`ized, controlled trial.
` However, we did not find
`12
`that nonoxynol 9 provided protection against gon-
`orrhea, as found in the earlier study. The previous
`study used the ratio of the number of events to the
`number of visits for each treatment group as the
`measure of effect. The number of events and person-
`years were not reported, so we cannot make a direct
`comparison with our results. This difference in out-
`come measures could account for some of the dif-
`ference in the two findings regarding gonorrhea. The
`nonoxynol 9 sponge used in the earlier study may
`also act as a physical barrier that prevents
`N. gonor-
` from infecting the endocervix.
`rhoeae
`As expected, there was an increase in genital ulcers
`in the nonoxynol 9 group. As was the case in the
`sponge study,
` the majority of lesions were external
`12
`rather than internal; the highest concentration of
`nonoxynol 9 is internal. However, in our study, the
`women who had genital ulcers did not have a higher
`rate of HIV infection, and there was no difference
`in the rate of infection between the women who had
`genital ulcers and used nonoxynol 9 and those who
`had genital ulcers and used placebo.
`There are many possible reasons for the fact that
`the nonoxynol 9 film did not prevent sexually trans-
`mitted diseases. The film may not be the optimal for-
`mulation; nonoxynol 9 may not be an adequate micro-
`bicide; the women may not have used the product
`correctly or as frequently as necessary (every time as
`opposed to most of the time); or condoms may have
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on October 7, 2016. For personal use only. No other uses without permission.
`
` Copyright © 1998 Massachusetts Medical Society. All rights reserved.
`
`Par Pharm., Inc., et al.
`Exhibit 1010
`Page 005
`
`

`

`NONOXYNOL 9 FILM TO REDUCE MALE-TO-FEMALE TRANSMISSION OF SEXUALLY TRANSMIT TED DISEASES
`
`TABLE 4. RATES OF GENITAL LESIONS IN THE PLACEBO AND NONOXYNOL 9 GROUPS.
`
`LOCATION OF LESION AND
`TREATMENT GROUP
`
`NO. OF
`WOMEN
`
`WOMAN-
`YEARS
`
`NO. OF
`EVENTS
`
`EVENT
`RATE*
`
`RATE RATIO
`(95% CI)†
`
`31.7
`38.1
`
`1.0
`1.3
`
`1.6
`2.9
`
`33.5
`42.2
`
`1.2 (0.9–1.6)
`
`1.3 (0.5–3.1)
`
`1.8 (0.7–4.9)
`
`1.3 (1.0–1.6)
`
`102
`119
`
`45
`
`6
`11
`
`107
`129
`
`322
`312
`
`388
`386
`
`383
`384
`
`319
`306
`
`393
`410
`
`393
`410
`
`393
`410
`
`393
`410
`
`Vulva
`Placebo
`Nonoxynol 9
`Vagina
`Placebo
`Nonoxynol 9
`Cervix
`Placebo
`Nonoxynol 9
`Any site
`Placebo
`Nonoxynol 9
`
`*The event rate is the rate per 100 woman-years.
`†The placebo group served as the reference category. CI denotes confidence interval.
`
`been used too frequently to allow the nonoxynol 9
`film to have a large effect. We believe that the women
`used the nonoxynol 9 film and that they used it cor-
`rectly. We provided monthly counseling about how
`to use the product and held regular community
`meetings that dealt with problems of film use and
`demonstrated correct use. When asked, the women
`were able to explain how to use the film properly.
`Although the women reported condom use more
`frequently than we had anticipated, HIV serocon-
`version still occurred in 94 women, which means
`that the study had a power of at least 90 percent to
`detect a 50 percent reduction in HIV infection with
`nonoxynol 9. Although a high rate of condom use
`may have attenuated the effect of nonoxynol 9, it is
`not likely to have reduced the effect to zero, as we
`found in this study. It is likely that condom use and
`film use were overreported in this study, as in many
`studies.26 We also found many more gonorrhea and
`chlamydia infections than HIV infections, and the
`study had a power of more than 90 percent to detect
`any effect on the incidence of these infections.
`Three pieces of circumstantial evidence indicate
`that the women used the barrier methods. First, be-
`tween the time we screened potential participants
`and the time we enrolled them, 15 women had
`seroconversion, a rate of 14 per 100 woman-years.
`The rate of seroconversion during the study was
`about 7 per 100 woman-years, indicating that the
`study intervention may have reduced the rate of HIV
`infection. Second, when we compared the women
`with a high rate of condom use (>75 percent) with
`those who had a low rate of condom use («50 per-
`cent), we found a rate ratio of 0.4, indicating some
`protection provided by the condom. Third, the in-
`crease in genital lesions in the nonoxynol 9 group
`may be evidence that the nonoxynol 9 was used.
`The particular product we tested did not show ev-
`
`idence of protection against sexually transmitted
`diseases, but the results cannot be overly general-
`ized. Other formulations of nonoxynol 9, as well as
`additional microbicidal compounds with different
`mechanisms of action, need to be tested as prophy-
`laxis against these diseases. Barrier methods con-
`trolled by women are urgently needed, and the efforts
`of the research community to provide women with
`multiple means of protection against sexually trans-
`mitted diseases should increase.
`
`Supported by grants from the Agency for International Development,
`the Mellon Foundation, and the National Institutes of Health (AI34714).
`The views expressed here do not necessarily reflect those of the funding
`agencies.
`
`We are indebted to the members of the Cameroonian study staff
`who made the completion of this complex study possible for their will-
`ingness to work hard and try innovative approaches whenever prob-
`lems arose; to the study participants for their great contribution and
`courage and for their willingness to submit to monthly examinations
`and interviews and use the film products despite knowing that some
`were using a placebo and that there was no guarantee that the
`nonoxynol 9 film would be protective; and to Dr. E. René Owona,
`Director of Community Health at the Ministry of Public Health,
`and Dr. Lazare Kaptué at the University of Yaoundé School of Med-
`icine for their assistance and guidance.
`
`REFERENCES
`
`1. Singh B, Cutler JC, Utidjian HMD. Studies on the development of a
`vaginal preparation providing both prophylaxis against venereal disease and
`other genital infections and contraception. II. Effect in vitro of vaginal
`contraceptive and non-contraceptive preparations on Treponema pallidum
`and Neisseria gonorrhoeae. Br J Vener Dis 1972;48:57-64.
`2. Bolch OH Jr, Warren JC. In vitro effects of Emko on Neisseria gonor-
`rhoeae and Trichomonas vaginalis. Am J Obstet Gynecol 1973;115:1145-8.
`3. Benes S, McCormack WM. Inhibition of growth of Chlamydia trachoma-
`tis by nonoxynol-9 in vitro. Antimicrob Agents Chemother 1985;27:724-6.
`4. Kelly JP, Reynolds RB, Stagno S, Louv WC, Alexander WJ. In vitro
`activity of the spermicide nonoxynol-9 against Chlamydia trachomatis.
`Antimicrob Agents Chemother 1985;27:760-2.
`5. Judson FN, Ehret JM, Bodin GF, Levin MJ, Rietmeijer CAM. In vitro
`evaluations of condoms with and without nonoxyn