The Big Picture
1. What is the aim of ASPIRE?
ASPIRE – A Study to Prevent Infection with a Ring for Extended Use, also known as MTN-020, is a Phase III clinical trial that seeks to determine whether a woman’s use of a vaginal ring containing the antiretroviral (ARV) drug dapivirine is a safe and effective method for protecting against HIV infection through vaginal sex. Vaginal rings are products designed to allow for the slow delivery of a drug or multiple drugs to cells inside the vagina over a period of weeks or months. The dapivirine ring being tested in ASPIRE is designed to be replaced every four weeks. As a potential method for preventing sexual transmission of HIV in women, rings represent another option besides microbicide gels that are used every day or at the time of sex. In addition to testing the ring’s safety and effectiveness, ASPIRE researchers also will assess whether women – and their partners – like using the ring, and, importantly, the extent to which women are able and willing to use such a product. ASPIRE will enroll approximately 3,476 women at several sites in Africa and is being conducted in parallel with a second trial, The Ring Study, led by the International Partnership for Microbicides (IPM), which developed the ring. As sister studies, the two trials are designed to provide the strength of evidence to support potential licensure of the dapivirine vaginal ring for preventing HIV in women.
2. What is unique about ASPIRE?
ASPIRE represents a major step forward in the evaluation of a promising female-controlled method that potentially could provide women with discreet, long-acting protection against HIV. Building on IPM’s previous research and as a complement to The Ring Study, ASPIRE is a critical component in a strategy that seeks to license the dapivirine ring. Significantly, ASPIRE and The Ring Study are the first effectiveness trials of a ring for HIV prevention and also of an ARV-based HIV prevention product using a drug other than tenofovir or tenofovir combined with the ARV emtricitabine.
3. Why is this study important?
Of the more than 34 million people living with HIV, half are women. The majority of women acquire HIV through heterosexual intercourse. In fact, women are twice as likely as their male partners to acquire HIV during sex, due in part to biological factors that make them more susceptible. Young women are especially vulnerable. In southern Africa, young women are up to five times more likely to become infected with HIV than young men. Efforts to promote abstinence, monogamy and the use of male condoms have not been enough to stop the HIV epidemic nor are these practical methods in most settings. There is an urgent need for effective prevention strategies that women can control themselves. Toward this end, vaginal microbicides are HIV prevention products being developed especially for use by women to help reduce their risk of HIV infection through vaginal sex.
To date, clinical trials have primarily focused on microbicides formulated as vaginal gels, with a gel based on the ARV tenofovir having been the most studied. In the CAPRISA 004 study, tenofovir gel used before and after sex reduced the risk of HIV infection by 39 percent. However, VOICE – Vaginal and Oral Interventions to Control the Epidemic – which was designed to test daily use of tenofovir gel, as well as daily use of an a ARV tablet, stopped testing tenofovir gel after an interim review of study data determined that while safe it was no better than a placebo for protecting against HIV in the women in the trial. In the meantime, a Phase III trial, FACTS 001, is testing the same tenofovir gel regimen used in CAPRISA 004, with results expected in 2015.
Some women may prefer taking a daily ARV tablet; some may prefer using a vaginal gel in association with sex, while others may prefer a microbicide in the form of a vaginal ring, which can be used monthly. Different approaches will appeal to different women, with the one that best suits individual needs or lifestyle more likely to be used. This is important, because a product only has a chance of being effective if it is used and used properly. As an effectiveness trial of a microbicide containing dapivirine – and of a product intended for extended use, ASPIRE will be especially important to ensure that women have different options for protecting themselves from transmission of HIV through vaginal sex.
4. Who is conducting the study?
ASPIRE is a study of the Microbicide Trials Network (MTN), an HIV/AIDS clinical trials network funded by the National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health, all components of the U.S. National Institutes of Health (NIH). Jared Baeten, M.D., Ph.D., of the University of Washington, U.S., is protocol chair; and Thesla Palanee, Ph.D., of the Wits Reproductive Health and HIV Institute, South Africa, is protocol co-chair.
5. When did the trial begin and how long will it last?
ASPIRE started enrolling participants in August 2012. The researchers expect to complete the study in 2014, with results available later that year or early 2015.
6. Where is ASPIRE being conducted?
Pending approvals by in-country regulatory authorities and research ethics boards, ASPIRE will be conducted at 16 MTN-affiliated sites in Malawi, Uganda, South Africa, Zambia and Zimbabwe.
7. What is a vaginal ring?
Vaginal rings are flexible products that fit comfortably high up inside the vagina and allow for the slow, continuous delivery of a drug or multiple drugs over a period of weeks or months. In the U.S. and Europe, vaginal ring products are licensed for both contraception delivery and hormone replacement.
8. What exactly is the dapivirine vaginal ring?
Researchers conducting ASPIRE are testing a vaginal ring containing 25mg of the ARV dapivirine. The ring is made of an elastic silicone material that measures 56mm (about 2 ¼ inches) in diameter and is 7.7mm thick (3/8 inch). The dapivirine ring is designed to be replaced every four weeks. When placed inside the vagina, the ring slowly releases the drug over time. Dapivirine, also known as TMC-120, is a type of ARV called a non-nucleoside reverse transcriptase inhibitor (NNRTI). NNRTIs bind to and disable HIV’s reverse transcriptase enzyme, a protein that HIV needs to make copies of itself. Although dapivirine was initially being developed by Tibotec Pharmaceuticals, a subsidiary of Johnson & Johnson based in Belgium, as an oral therapeutic agent to be used in the treatment of HIV, dapivirine is a promising candidate for development as a microbicide due to its favorable safety profile as well as its physical and chemical properties. In 2004, Tibotec (now Janssen R&D Ireland, one of the Janssen pharmaceutical companies of Johnson & Johnson) assigned a royalty-free license to IPM, a non-profit product development partnership based in Silver Spring, Md., to develop dapivirine as a vaginal microbicide for the prevention of HIV in developing countries. Since then, 16 clinical safety studies of dapivirine, formulated as either a vaginal gel or a vaginal ring, have been conducted by IPM and its partners. As the regulatory sponsor and license holder of the dapivirine ring, IPM will be providing both the placebo rings and the rings containing dapivirine for use in ASPIRE.
9. How is ASPIRE designed?
ASPIRE is a Phase III trial designed to evaluate the safety and effectiveness of the dapivirine vaginal ring for preventing the sexual transmission of HIV in women. The study will enroll approximately 3,476 HIV-negative women who will be randomly assigned to use either the dapivirine ring or a placebo ring that looks the same but contains no active drug. Participants will insert a new ring every four weeks during their monthly clinic visit. Women will use their assigned product for at least one year, some for as long as two years. As part of the study, all participants will receive ongoing HIV risk reduction counseling, condoms and diagnosis and treatment of sexually transmitted infections (STIs). In addition to determining the ring’s safety and effectiveness, ASPIRE is designed to assess women’s adherence to and acceptability of the ring. Researchers will also try to determine if there is a relationship between drug levels in cells and tissue and HIV acquisition, as well as the nature and frequency of HIV drug resistance among those women who, despite the HIV prevention measures provided to all participants, acquire HIV during the study.
10. What other studies have been conducted of the dapivirine vaginal ring?
ASPIRE is the culmination of a large body of research led by IPM looking at the dapivirine ring as an alternative HIV prevention option for women. These studies have shown the dapivirine ring can deliver high concentrations of active drug to vaginal tissue for a month or longer, with only trace amounts of the drug being absorbed elsewhere in the body. Furthermore, studies to date have found that use of the dapivirine ring is safe and well-tolerated by women, and that among women in Africa, the vaginal ring itself is highly acceptable as a potential method for HIV prevention. In studies to date, the most common side effect associated with the dapivirine vaginal ring has been headache. Some women have also experienced vaginal discomfort or bleeding between menstrual periods.
As part of its strategy to license the ring, IPM is conducting The Ring Study, also known as IPM 027, in parallel with ASPIRE. The Ring Study, which began enrolling women in March 2012, will collect additional long-term safety and efficacy data about the dapivirine ring among approximately 1,650 women at four sites in South Africa and one in Rwanda. Several smaller studies of the ring are being planned, including studies that will be conducted by the MTN to evaluate the ring’s safety in adolescents and postmenopausal women, and others that IPM will be conducting looking at condom compatibility and drug interactions.
11. Why the need for both ASPIRE and The Ring Study, and as efficacy trials, are they any different?
As sister studies, ASPIRE and The Ring Study are designed to collect the strength of evidence needed by regulatory authorities to consider the potential licensure of the dapivirine vaginal ring for preventing HIV in women. By conducting the trials in parallel, researchers will be able to obtain answers to key questions more quickly. Both ASPIRE and The Ring Study will evaluate the long-term safety and effectiveness of the dapivirine ring for preventing HIV among women when used once a month. For its part, ASPIRE will enroll approximately 3,476 HIV-negative women, ages 18-45, who will be randomly assigned in equal number to use either the dapivirine ring or a placebo ring. Women will use their assigned product for at least one year, some for as long as two years. The Ring Study will enroll approximately 1,650 HIV-negative women, ages 18-45. Women will be randomly assigned to use either the dapivirine ring or a placebo ring, but twice as many will be randomized to use the dapivirine ring. Women in The Ring Study will use their assigned ring for two years.
12. Are there plans to make the dapivirine ring widely available after these studies?
If the results of a package of studies, of which ASPIRE and The Ring Study are the centerpiece, find the ring is safe and effective, IPM intends to seek product approval from the European Medicines Agency, the U.S. Food and Drug Administration (FDA) and the South African Medicines Control Council (MCC) and other African regulatory agencies. If the ring is subsequently approved, IPM is committed to making it available at the lowest possible cost in countries where women urgently need tools to protect themselves against sexual transmission of HIV.
13. What if tenofovir gel is approved and/or oral pre-exposure prophylaxis is implemented for preventing HIV in women? What would be the impact on ASPIRE?
When researchers started planning ASPIRE it seemed possible that tenofovir gel could be approved for use during the time the trial was still underway. That’s because following the promising results of CAPRISA 004, which found tenofovir gel 39 percent more effective than placebo gel when used before and after sex, the U.S. FDA indicated that it would review data from VOICE as the second pivotal trial to support possible licensure of tenofovir gel. However, VOICE closed the tenofovir gel arm of the trial in November 2011 after a routine review by the study’s Data and Safety Monitoring Board (DSMB) indicated that while the gel was safe, it was not effective in the women in the study, who were asked to use the gel every day. Although tenofovir gel is being evaluated in FACTS 001, a Phase III trial testing the same regimen of tenofovir gel used in CAPRISA 004, results are not expected until 2015. Should tenofovir gel prove safe and effective in FACTS 001 (when used before and after sex) and regulatory approval follow, the earliest that tenofovir gel could be introduced would be 2016 or 2017 – well after ASPIRE has concluded.
Results of trials testing once-daily use of an oral ARV tablet – an approach called oral pre-exposure prophylaxis, or PrEP – and the subsequent FDA approval of Truvada as PrEP for HIV prevention, have also stimulated discussion about the development of World Health Organization (WHO) and UNAIDS guidelines on its use in certain at-risk populations. At the present time, WHO has issued guidance on PrEP for serodiscordant couples (in whom one partner is HIV-infected) and men who have sex with men, which recommends its use in the context of demonstration projects. There are many questions and challenges still to be addressed, and results from ongoing trials, such as VOICE, are not yet available. The research team conducting ASPIRE understands that, depending on the timing, a change in a country’s national HIV prevention program could necessitate making modifications to ASPIRE as well. The team will closely monitor relevant national policies and the global HIV prevention landscape and continue to engage with policy makers, governments and other stakeholders about these important issues throughout the duration of study.
At the Trial Site
14. What kind of approvals are needed to conduct the study?
ASPIRE has undergone extensive and rigorous review by NIAID and has also been reviewed by the U.S. FDA. However, before any site can begin enrolling women into the study, approvals are required of government and regulatory authorities in the trial site country and by the site’s Institutional Review Board (IRB) or Ethics Committee (EC). IRBs and ECs ensure that studies are scientifically valid and ethically sound and provide oversight throughout the duration of the trial.
15. Who may participate in ASPIRE?
Women between the ages of 18 and 45 who are sexually active and HIV-negative may be eligible to enroll in ASPIRE, provided they meet other study inclusion criteria. For instance, women who are pregnant or breastfeeding, or intend on getting pregnant, cannot participate in ASPIRE.
16. Will women participating in ASPIRE provide informed consent?
Yes. Women who volunteer to join ASPIRE are educated about all the study procedures, any possible risks, benefits and alternatives to participation as well as the study’s time requirements. Study staff also explain that women do not have to take part in the study and can leave it at any time, without consequence. This process is called “informed consent” and it occurs prior to screening for ASPIRE, again at enrollment, and continues throughout the duration of the study. Information is provided in simple terms and translated into local languages. Site community educators and Community Advisory Board (CAB) members also play important roles in helping prospective participants understand the study.
17. Will women be taught how to insert and remove the ring?
Participants will learn how to insert and remove the ring when they first enroll into the study and will receive additional guidance at monthly follow-up visits as needed. Site staff will counsel participants on the ring’s correct use. Specifically, participants will be asked to refrain from removing the ring (except as directed) between study visits and instructed on how to reinsert the ring should it come out accidentally. They will be discouraged from using intravaginal medications or products, such as lubricants, douches, spermicides or diaphragms because the safety of these products and practices in combination with use of the dapivirine ring is currently not known.
18. What will be done to ensure the safety of participants in ASPIRE?
ASPIRE was designed based on rigorous international medical practice and ethical standards. It is being conducted with numerous measures to protect the safety and well-being of participants. Potential volunteers are carefully screened by study staff to ensure that only women for whom it would be safe to participate are enrolled. Clinical teams at the trial sites perform thorough evaluations on the health, safety and welfare of participants at each study visit. A team at the MTN statistical and data management center (SDMC) assesses incoming reports on a daily basis; and an ASPIRE protocol safety review team (PSRT) provides regular monthly oversight. The PSRT includes three additional MTN physicians – two specializing in infectious diseases and HIV and the other in obstetrics and gynecology – whose sole responsibilities are to ensure that everything possible is being done to monitor and protect the safety of participants. Regular reviews will also be conducted by an independent Data and Safety Monitoring Board (DSMB) that oversees clinical trials funded by NIAID to ensure that participants are not being adversely affected by the study or study products. If the DSMB has any safety concerns, it may, at any time, recommend that the study modify its procedures or be discontinued. In addition, the DSMB may recommend halting the trial if there is compelling evidence for a product’s effectiveness or if it becomes clear that the trial cannot answer whether a product is effective.
19. What happens if a participant becomes HIV-positive while enrolled in ASPIRE?
All women in ASPIRE will receive comprehensive HIV prevention counseling and services throughout the trial that include free condoms, risk-reduction counseling, regular HIV testing and other provisions. Despite these intensive efforts, a participant could become infected if she has unprotected sex with a partner who has HIV. Women in the trial who test positive for HIV will be taken off study product immediately because continuing its use could increase the risk of the virus becoming resistant to dapivirine and similar ARVs; and they will be counseled and referred by study staff to local HIV care and support services. Although off study product, women will be encouraged to remain in the ASPIRE study and continue with routine study visits. When possible, they will also be referred to other local research studies for HIV-infected women. In addition, ASPIRE participants who become infected will be invited to participate in another MTN study called MTN-015. MTN-015 does not provide HIV treatment, but with a participant’s permission, researchers can maintain close contact with her primary treatment provider and share results of laboratory tests that are performed as part of the study, which may suggest modifications to her treatment and help improve the level of care.
20. How could a woman become HIV-positive while taking part in an HIV prevention trial?
In sub-Saharan Africa, where ASPIRE is being conducted, a woman’s risk for acquiring HIV through sexual intercourse is greater than in any other part of the world. Participants in HIV prevention trials like ASPIRE are reminded of the fact that the product being tested has not been proven effective and that not all women in the study may be using an active product. To reduce the risk of HIV for women participating in its trials, MTN researchers provide trial participants free condoms, frequent HIV testing and HIV risk-reduction counseling, including on the correct and consistent use of condoms, and provide routine testing and treatment for STIs. Despite these intensive, ongoing efforts, a woman who participates in a trial like ASPIRE could acquire HIV if she has unprotected sex with a partner who is infected with the virus.
21. Is there concern that women who become HIV-infected will develop drug resistance to dapivirine?
It’s important to understand that drug resistance is possible only in someone infected with HIV, and the study’s primary interest will be in reducing the risk of HIV infection in all women who participate. If a woman becomes infected despite the study’s efforts, safeguards will be in place to minimize the potential for drug resistance. For instance, women in ASPIRE will be tested for HIV at every monthly visit. If a test indicates that a woman has acquired HIV, staff will immediately stop her use of study product, because its continued use could potentially increase the chance that virus will become resistant to the drug. Women testing positive for HIV in ASPIRE will be monitored for resistance, even after stopping product use, so that if identified, it can be managed appropriately by those treating the infection. ARV drugs in the same class as dapivirine (NNRTIs) are used in the treatment of HIV. One potential advantage dapivirine may have is that it remains potent even in the presence of common HIV strains with resistance. Thus, dapivirine may offer greater protection against infection. The ASPIRE trial will help to understand the nature and frequency of drug resistance among women who become infected while enrolled in the study.
22. What will ASPIRE be doing to reduce the risk of drug resistance?
ASPIRE will include several safeguards to minimize the potential for drug resistance. Researchers will screen all prospective participants for HIV infection to avoid enrolling anyone who is already HIV-infected, and women who enroll in the study will undergo monthly HIV testing so that investigators can quickly identify women who may have acquired HIV and immediately stop their use of the ring. Based on current understanding about viral resistance, ASPIRE researchers believe that these and other procedures will help minimize the potential that a drug-resistant virus will develop or persist in women who acquire HIV while in the study.
23. Will ASPIRE provide antiretroviral therapy, or ART, to women who acquire HIV?
MTN receives funding to conduct clinical trials only, and is not permitted to provide HIV treatment. However, all MTN trial sites are required to have agreements with local service providers so that if a study participant acquires HIV she can be referred to the appropriate services and care in her community. In addition, site staff offer women the opportunity to participate in another MTN study, MTN-015. As a long-term observational study, MTN-015 does not provide HIV treatment, but frequent laboratory tests indicating how the disease is progressing and how women are responding to treatment can help local treatment providers better manage the clinical care of these women.
24. What is adherence and why is it so important?
In the context of HIV prevention research, adherence refers to a person’s willingness or ability to correctly and consistently follow a prescribed regimen. Adherence is a critical component to the success of any clinical trial evaluating a particular intervention, because if a high percentage of participants fail to follow the study’s regimen, it will be difficult to know the true effectiveness of a product or approach. Adherence is important because even the most effective product will not provide benefit if it is not used or not used properly. Indeed, earlier PrEP trials such as iPrEx and CAPRISA 004 showed that the study product was more effective in those who used it regularly. In iPrEx, which involved men who have sex with men, there were nearly 44 percent fewer HIV infections among participants who were assigned to take Truvada every day than among those who were assigned to a placebo tablet. However, in the men who took the drug more than 90 percent of the time (according to pill counts and self-reports) there were nearly 73 percent fewer HIV infections, and in the men whose blood levels of drug suggested that they took the pills regularly, HIV risk was reduced by more than 90 percent. Similarly, CAPRISA 004 found tenofovir gel reduced the risk of HIV by 39 percent among women who used it before and after vaginal sex compared to women who used a placebo gel, but among women who were considered “high adherers,” risk was reduced by 54 percent compared to the placebo group.
The dapivirine ring being evaluated in ASPIRE is a longer-acting product – to be used by women for four weeks at time – which may be easier and more convenient for women to use consistently. Still, participants will be counseled at each visit about the importance of adhering to the study regimens and safer sex practices. They will also be reminded that the ring being tested has not been proven effective in preventing HIV, and that not all women participating in ASPIRE will be using an active product.
25. How will adherence be measured in ASPIRE?
ASPIRE researchers recognize the importance of understanding women’s adherence to use of the dapivirine ring. Even the most effective prevention approach will not be effective if it’s not used or not used properly. Adherence will be evaluated using different measures in ASPIRE, including face-to-face interviews and the use of Audio-Computer Assisted Self Interviewing (ACASI), which allows participants to answer questions about condom use, sexual behavior and product use – such as whether they were able to keep the ring in place for four weeks, and if not, why. Blood and vaginal fluid samples taken from participants at different times in the study will also help determine how well participants followed the study regimens by measuring the amount of drug present.
26. What happens to women who become pregnant or are breastfeeding?
Pregnant women and women who are breastfeeding at the time of screening will not be able to join ASPIRE. Researchers don’t yet know how dapivirine might affect a woman’s pregnancy or the development of her fetus, or her baby if she continues to use the ring while breastfeeding. Women who enroll must not be planning to become pregnant during the study and must use effective contraception and have monthly pregnancy tests throughout the trial. If a participant becomes pregnant during the study, she will stop use of the ring, but will remain in the study and continue with all trial site visits. She will also be referred by study staff to available sources of medical care and other services that she or her baby may need. Depending on the timing of pregnancy relative to the study’s progress, some women may be able to resume using the ring, provided they are no longer breastfeeding. Women who become pregnant will also be invited to participate in MTN 016 or EMBRACE (Evaluation of Maternal and Baby Outcome Registry After Chemoprophylactic Exposure) study, a first-of-its-kind observational study of women who become pregnant during an HIV prevention trial and pregnant women who have participated in other MTN safety studies.
27. What are the medical benefits for women participating in the study?
Study participants will receive free laboratory tests and physical and pelvic exams, HIV prevention counseling and free condoms. STI risk-reduction counseling, testing and treatment are provided at no charge to women. HIV testing and STI treatment will also be provided to their partners. In addition, ASPIRE will provide effective barrier and hormonal contraception and monthly pregnancy and HIV testing. Participants who acquire HIV during the trial will be counseled appropriately and receive referrals to community-based programs for care and support. While they will no longer be able to use their assigned study ring, women will have the option to remain in the trial and receive all scheduled safety evaluations. For medical issues that become apparent during trial participation and fall beyond the scope of management of the clinical trial site, women will be referred to local service providers for ongoing treatment, management and care.
28. If women participating in this study use condoms, how will you know if the ring is effective for preventing HIV?
In order to reduce the risk of HIV for all women in the trial, researchers provide participants free condoms and HIV risk-reduction counseling, including education on the correct and consistent use of condoms, and routine testing and treatment for STIs. If every single participant used a condom for every act of sexual intercourse during the course of the study, it would be nearly impossible for researchers to evaluate the effectiveness of the ring. Although we know that the use of male condoms is the best known way to prevent HIV, unfortunately, as is true in the “real world,” women may not be able to use condoms all the time, for a variety of reasons. Once the study is completed, results will be analyzed taking into account how often women reported using condoms each time they had sex.
29. What if another HIV prevention approach becomes widely available during this trial– would women in the trial have access?
As part of the study, all enrolled participants will receive individual HIV counseling, condoms, risk reduction counseling and treatment for STIs. If, during the course of the study, other new prevention strategies are found to be effective and are also incorporated into national HIV prevention policies, study participants will be counseled about these interventions, and either be offered them by the site or referred to local centers with appropriate expertise, in accordance with WHO/UNAIDS guidelines and local HIV prevention practice and standards.
30. Why is ASPIRE only being conducted in Africa?
The MTN has clinical trial sites in Africa, India, Peru, Thailand and the United States, but not all of these sites are in places where the rates of new HIV infections are as high as they are in Africa. In places where the risk for HIV infection is high, researchers can determine more quickly and with greater certainty whether a certain product is working. More importantly, women in sub-Saharan Africa represent the largest and fastest growing at-risk population for HIV, and they have the most to gain if this trial or any other trial identifies a safe and effective method for preventing HIV.
31. How is ASPIRE involving the community?
True community participation in HIV prevention research requires a level of ownership throughout the research process. Understanding the purpose, methods and limitations of clinical research is also vital for meaningful community input into study design and implementation. As such, all MTN trial sites have active community engagement programs with local non-governmental organizations, activist groups, journalists, local physicians, health department officials and other stakeholders; and during the development of an MTN protocol and throughout implementation, trial site Community Advisory Boards (CABs) play an especially important role. At a broader level, MTN’s Community Working Group (CWG), comprised of community educators and CAB members from each clinical research site, has and will continue to be actively involved in the development of community education strategies and the informed consent process and in providing input about different study procedures. The MTN has also engaged and will continue to engage with leading African advocates and civil society representatives about the design and conduct of ASPIRE, especially in the context of a changing HIV prevention trials landscape.
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More information and materials about ASPIRE is available at http://www.mtnstopshiv.org/news/studies/mtn020