Browsing by Author "Taylor, Douglas."

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An adaptive design to bridge the gap between phase 2b/3 microbicide effectiveness trials and evidence required for licensure.
(Sage., 2012) Taylor, Douglas.; Grobler, Anna Christina.; Abdool Karim, Salim Safurdeen.
Background. Vaginally and rectally applied microbicides are being developed to help prevent sexual acquisition of HIV. Due to the lack of surrogate outcomes, the path toward licensure typically moves directly from expanded safety studies to expensive Phase 2b/3 trials with rare incident infection outcomes. The need to confirm an initial trial’s significant finding can lead to serious delays in implementing essential programs to reduce the spread of HIV. Purpose. To propose an adaptive design where a Phase 2b/3 study powered to detect a clinically meaningful effect with evidence of one trial (observing one-sided p < 0.025) is allowed to expand by a prespecified, feasible amount if interim data suggest the chance of further achieving a more robust evidence threshold ( p < 0.001, potentially sufficient for licensure from a single trial) is promising. Methods. As an example, prespecified conditional power criteria are used to determine whether a 90-event trial with 90% power to detect a 50% reduction in risk should be expanded to 130 events. Asymptotic results and simulations are used to assess false-positive error rates and other operating characteristics of the design. Results. False-positive error rates can be controlled at the desired 0.025 and 0.001 levels with appropriate choice of critical values or expansion criteria. The chance of achieving robust evidence can approach that of a 130-event trial with traditional stopping boundaries (controlling a = 0.001) but with substantially lower expected size for plausible effectiveness levels. Limitations. Conditional power calculations assume the interim estimate of effect is an unbiased estimate for the remainder of the trial, an assumption which may not hold if product adherence varies over time. Observing a measure of effect with p < 0.001 may not be sufficient for licensure. A decision to expand the trial would be informative to investigators regarding the interim effect size. Conclusions. A moderate increase in trial size can make the difference between a study with good power to detect a clinically meaningful effect and one which may reasonably obtain the robust evidence required for regulatory bodies and public health programs to consider making a new microbicide available to persons at risk of HIV infection. The proposed design allows for this possibility while not requiring investigators to make an up-front commitment to a prohibitively large trial.
Assessing adherence in the CAPRISA 004 tenofovir gel HIV prevention trial: results of a nested case–control study.
(Springer., 2014) MacQueen, Kathleen M.; Weaver, Mark A.; van Loggerenberg, Francois.; Succop, Stacey M.; Majola, Nelisile.; Taylor, Douglas.; Abdool Karim, Quarraisha.; Abdool Karim, Salim Safurdeen.
Abstract available in pdf.
Challenges in HIV-prevention microbicide research.
(American Association for the Advancement of Science., 2008) Harrison, Polly.; Mellors, John W.; Richardson, Barbra Ann.; Masse, Benoit.; Abdool Karim, Quarraisha.; Abdool Karim, Salim Safurdeen.; Cates, Ward.; Coletti, Anne S.; Derbyshire, Janet.; Dorflinger, Laneta J.; Feldblum, Paul J.; Gabelnick, Henry.; Halpern, Vera Grigorieva.; Jespers, Vicky.; Kharsany, Ayesha Bibi Mahomed.; McCormack, Sheena.; Nunn, Andrew.; McGowan, Ian M.; Omar, Rabeea F.; Padian, Nancy S.; Pedneault, Louise.; Robbiani, Melissa Pope.; Sailer, James.; Taylor, Douglas.; Tolley, Elizabeth E.; Van Damme, Lut.; Vermund, Sten H.; van de Wijgert, Janneke.
No abstract available.
Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women.
(American Association for the Advancement of Science., 2010) Abdool Karim, Salim Safurdeen.; Abdool Karim, Quarraisha.; Fröhlich, Janet Ann.; Grobler, Anna Christina.; Baxter, Cheryl.; Mansoor, Leila Essop.; Kharsany, Ayesha Bibi Mahomed.; Sibeko, Sengeziwe.; Mlisana, Koleka Patience.; Omar, Zaheen.; Gengiah, Tanuja Narayansamy.; Maarschalk, Silvia.; Arulappan, Natasha.; Mlotshwa, Mukelisiwe.; Morris, Lynn.; Taylor, Douglas.
The Centre for the AIDS Program of Research in South Africa (CAPRISA) 004 trial assessed the effectiveness and safety of a 1% vaginal gel formulation of tenofovir, a nucleotide reverse transcriptase inhibitor, for the prevention of HIV acquisition in women. A double-blind, randomized controlled trial was conducted comparing tenofovir gel (n = 445 women) with placebo gel (n = 444 women) in sexually active, HIV-uninfected 18- to 40-year-old women in urban and rural KwaZulu-Natal, South Africa. HIV serostatus, safety, sexual behavior, and gel and condom use were assessed at monthly follow-up visits for 30 months. HIV incidence in the tenofovir gel arm was 5.6 per 100 women-years (person time of study observation) (38 out of 680.6 women-years) compared with 9.1 per 100 women-years (60 out of 660.7 women-years) in the placebo gel arm (incidence rate ratio = 0.61; P = 0.017). In high adherers (gel adherence > 80%), HIV incidence was 54% lower (P = 0.025) in the tenofovir gel arm. In intermediate adherers (gel adherence 50 to 80%) and low adherers (gel adherence < 50%), the HIV incidence reduction was 38 and 28%, respectively. Tenofovir gel reduced HIV acquisition by an estimated 39% overall, and by 54% in women with high gel adherence. No increase in the overall adverse event rates was observed. There were no changes in viral load and no tenofovir resistance in HIV seroconverters. Tenofovir gel could potentially fill an important HIV prevention gap, especially for women unable to successfully negotiate mutual monogamy or condom use.