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Newsletter Issue #18, March 2015

INA-RESPOND Secretariat. Badan Litbangkes, Kemenkes RI, Building 4, Level 5,
Jl. Percetakan Negara No. 29, Jakarta, 10560. Phone: +62 21 42879189. A GLIMMER OF HOPE FOR TUBERCULOSIS TREATMENT
by dr. Retna Mustika Indah. Before knowing streptomycin, isoniazid, and other famous anti-tuberculosis (TB) drugs, weapons against TB were blunt at best. For over 50 years, doctors treated TB patients at sanatoriums with a regimen of strict rest and fresh air. When long-term results failed to produce, physicians added collapse therapy to the treatment. That invasive procedure, however, resulted in a variety of World TB Day is celebrated every year complications. Past article from early 2000 mentioned pleural calcification by the health organizations, NGOs, with pyogenic empyema and pleural calcification with non-resolvable pneumothorax as the complications of this procedure. organizations including other health agencies to raise the awareness among Anti-Tuberculosis drugs are cornerstones of tuberculosis treatment. But, common public all across the world treating TB is not a cakewalk. Since the era of chemotherapy began, about the epidemic disease by resistance to anti-tuberculosis drugs has been a problem. Streptomycin organizing various campaigns and resistance was shortly recognized in 1947 after the introduction of effective related activities such as debates on TB anti-TB chemotherapy, but the emergence of Multidrug-resistant prevention and cure, etc. This month, tuberculosis (MDR-TB) became widely acknowledged as a global problem our newsletter features potential TB after a dramatic outbreak in the early 1990s. After that, resistance to anti-TB drugs. What are they? Find the drugs is considered as a potentially catastrophic challenge to global public information here! Dr. Anthony S. Fauci in one of his articles wrote that the most critical need for
patients with drug-resistant TB is access to new drugs. For many years,
scientists have tried to build a better mousetrap on tuberculosis treatment.
Ultimately after decades of quiescence in the development of anti-TB
medications, we finally have potential multiple new anti-TB drugs, which
have novel and unique mechanism of action. Bedaquiline and Delamanid
have been conditionally approved for drug-resistant TB treatment, while
other novel compounds such as PA-284 and TBA 354 have been evaluated.
These newly developed drugs are mainly intended for Drug Resistant TB
treatment.
Do you know what a biorepository is and how to establish one? This month's Bedaquiline. For the first time in over 40 years, a new TB drug with a novel newsletter covers brief overview on
mechanism of action is available, and was granted accelerated approval by some of the essential issues in the United States Food and Drug Administration in December 2012 and by establishing biorepository such as the The European Medicines Agency (EMA) in March 2014. This drug actively infrastructure, environment, and acts on both actively replicating and dormant mycobacteria by inhibiting the approval from study subjects. Moreover, mycobacterial ATP synthase. The clinical evidence showed that adding this where does our network stand on this diaryquinolines class to a standard background MDR-TB treatment regimen issue? And how can we contribute? Read significantly decreased the time to sputum culture conversion and the article and find out for yourself. nonsignificantly prevented the acquisition of additional resistance to other companying drugs. [Continue to page 4] Page 1 of 6

Newsletter Issue #18, March 2015

Studies' Progress
and Update
by dr. Anandika Pawitri, dr. Herman Kosasih, dr. Nugroho Harry Susanto, dr. Retna Mustika. AFIRE STUDY
Picture 1 INA-RESPOND Office Warming, NIHRD, Jakarta
Entering the first week of March in 2015, 2864 patients had been screened. 859 subjects had been enrolled (499 adults and 360 children). Description of screening and enrollment progress can be seen in the chart below: Detailed screening and enrollment progress is available in portal folder: Studies INA101 Screening progress.pd f or go to the following link *510– RSUP dr Hasan Sadikin, Bandung 550 – RSUP dr Wahidin, Makassar 520 – RSUP Sanglah, Denpasar 560 – RSUP dr Kariadi, Semarang 530 – RSUPN dr Cipto Mangunkusumo, Jakarta 570 – RSUD dr Soetomo, Surabaya 540 – RSPI Prof Dr Sulianti Saroso, Jakarta 580 – RSUP dr Sardjito, Yogyakarta For further information on this study,go to Sepsis Study has officially started in While waiting for the Implementation Makassar site, RSUP dr. Wahidin Arrangement to be set, the Secretariat continues Sudirohusodo, started the enrollment on February 26. preparing site 590 (Persahabatan hospital). The The enrollment period is until the end of 2015. As for subcontract agreement is expected to be signed by Yogyakarta site, RSUP dr. Sardjito, the Secretariat The Director of Persahabatan Hospital on the 4th completed the first Site Preparation (SPV) on March week of March. Upon approval, the secretariat will 3-4, and on March 19 – 20 the second SPV will be conduct SPV. The INA102 CRF Completion Guideline conducted to cover mostly practical issues in version 1.0 and annotated CRF version 1.0 have been laboratory and how to complete CRF. As the data approved, and the OpenClinica screen for INA102 is completion in Sepsis Study is quite different than that being developed. Data Manager will do the User in AFIRE study, RA for Sepsis Study has to master not Acceptance Test after the INA102 OpenClinica only paper CRF but also electronic CRF. screen is ready. Moreover, site is also preparing the room that will be Jakarta site, RSUPN dr. Cipto Mangunkusumo, is still used for the INA-RESPOND office at site. in the middle of IRB process for protocol submission. Page 2 of 6

Newsletter Issue #18, March 2015

ReDefine STUDY
Under this study, INA-RESPOND is involved in the study initiation visit, study monitoring, and DSMB. The site started screening in December 2014 and as of February 27 a total of 13 subjects was enrolled and 3 SAEs occurred. The 3 SAEs cases were reported to the local EC and the DSMB Chair and members immediately upon occurrences. The first SAE case was reported to the Indonesia FDA (BPOM) on February 16; the second and third SAE cases will be reported to BPOM on 11 March – Ms. Eni Yuarni
March 9.The DSMB members are planning their discussion via teleconference on March 11. Research and Development / Badan Litbangkes) The 2nd Site Monitoring Visit (SMV) is scheduled for April 15-17. 20 March – Mr. Antonius Pradana,
S.Kom (INA-RESPOND Secretariat)
26 March – dr. Fritzie Cheria
Save The Date
(INA101 Research Assistant at site World TB Day, falling on March 24 each year, is
designed to build public awareness that 27 March – Andi Arahmaniar, Amd,
tuberculosis today remains an epidemic in much AK (SEA050 Lab Technician at site of the world, causing the deaths of nearly one- 42 – Makassar) and-a-half million people each year, mostly in 28 March – dr. Tri Wibawa Ph.D
developing countries. (INA101 Site PI at Site 580) The main sub-theme and message for this year is "Reach, Treat, Cure
Everyone". World TB Day theme encourages local and state TB
programs to reach out to their communities to raise awareness about On this occasion, we would like to TB. We don't have to fight TB alone; we should partner with others who express our sincere gratitude for dr.
are also caring for those most at risk for TB such as people with HIV infection or diabetes, and the homeless. Everyone has a role in ensuring Assistant at site 510) who has left that one day TB will be eliminated. her post. Thank you for your time and dedication to the INA-RESPOND In light of this, the National Institute of Health Research and Development is holding a TB day event on March 11 – 12 in Ars Longa Auditorium, Building 3 floor 3, NIHRD.
Network Steering
FOR MORE INFORMATION Committee Meeting and
Please contact Mr. Dedy Network Annual Meeting
Hidayat or Ms. Yayu The next NSC Meeting will be held Nuzulurrahmah at +62 21 on 29-30 April 2015 in Jakarta at
42879189 ext. 102 or 112 Hotel JS Luwansa, Jl. HR. Rasuna during office hours (08.00 – 16.00) Said Kav. C-22, Jakarta Pusat, Daerah Khusus Ibukota Jakarta 12940, Indonesia. Page 3 of 6
Newsletter Issue #18, March 2015

[A GLIMMER OF HOPE FOR TUBERCULOSIS
TREATMENT]
Delamanid. A nitroimidazo-oxazole was granted
generation antituberculosis nitroimidazole following conditional approval by EMA in April 2014. an extensive medicinal chemistry effort. TBA-354 has Information about this new drug, however, remains narrow spectrum and bactericidal in vitro against limited since it has only been through Phase IIb trial and studies for safety and efficacy. Sputum culture tuberculosis, with potency similar to that of conversion rates in MDR-TB patients improve when Delamanid and greater than that of PA-824. Having Delamanid is added to existing regimen. However, demonstrated advantages over the first-generation the optimum duration, dose, and schedule for compounds, TBA-354 entered clinical testing in 2015. administering Delamanid still remain a question. Furthermore, Delamanid's ability to protect against emergence of resistance to other co-administered anti-TB drugs regimens demand to be studied. It is unclear which agents would be the most effective and least toxic when paired with Delamanid to treat drug-resistant TB. The phase 1 randomized trial aims to evaluate the safety and tolerability of single oral doses of TBA‐354 PA-824. Another synthesized nitroimidazole that
when it is administered to healthy adult subjects. The potentially contributes to novel regimens for TB is first human trial of TBA-354 is expected to be PA-824 (Pretomanid). The novel mechanism of action completed by the end of 2015, by enrolling 48 healthy of PA-824 involves inhibition of the synthesis of adult volunteers at one study center in the United mycobacterial proteins and lipids, but not nucleic States. The Phase 1 program includes two clinical acids. A triad of PA-824, Moxifloxacin, and studies, a single ascending dose study and a multiple Pyrazinamide (PaMZ) is potentially suitable for ascending dose study. Six cohorts of 8 subjects each treating drug-sensitive and drug-resistant TB in 4 (6 active and 2 placebo), with one cohort crossing months, drastically improving treatment. This can be over to assess food effect, are planned for evaluation. considered as a first step towards developing a single Safety will be assessed throughout the study; serial treatment regimen for both TB. PaMZ was the first ECGs and serial blood samples will be collected for novel multi-drug TB treatment to undergo clinical the safety and PK assessment of TBA‐354. Dose testing in the new regimen development paradigm. escalation to the next cohort will not take place until This multiple agents are expected to contribute in the Sponsor, in conjunction with the Principal reducing the time needed to develop new Investigator, has determined that adequate safety, antituberculosis regimens. This regimen is projected tolerability, and PK from the previous cohort have to be able to be effectively administered alongside been demonstrated to permit proceeding to the next common ARV treatments, therefore improving treatment options for patients co-infected by TB and HIV. Additionally, PaMZ regimen can be administered All of these new contrivances bring a glimmer of hope in a fixed dose for all patients, and will therefore be for tuberculosis treatment all over the world. In the simpler for health systems to deliver and for patients coming decade, there are likely some newly developed drugs resulted from many high quality trials. As one of the leading clinical research networks TBA-354. The Global Alliance for TB Drug
on infectious disease in Indonesia, INA-RESPOND is Development has pursued the synthesis and prepared to conduct high quality clinical research. evaluation of over one thousand nitroimidazole Let's just say, we are ready to take up the challenge analogs. To maximize the potential of nitroimidazole and toss our hat into the ring. class, TBA-354 was selected as a potential next- Page 4 of 6
Newsletter Issue #18, March 2015

Establishment of a Biorepository:
Brief Overview of Some Essential Issues
by Agus Dwi Harso, Dona Arlinda, M. Karyana The terminology of "biorepository" maybe not be and contingency plans are necessary. Biorepository is known so well in Indonesia. However, the concept of a controlled environment. Secure funding, quality storing biological specimens for future researches has assurance, quality control, SOPs, internal and been grasped by institutions such as the National external audits as well as documentation and Institute of Health Research and Development reporting need to be put in place. As part of cold- (NIHRD) in conjunction to its large-scale studies. chain of custody, the specimen collector (or According to guideline of the International Society for investigator), handler and transporter must comply Biological and Environmental Repositories (ISBER) in with Good Clinical and Laboratory Practice (GCLP) 2012, biorepository is an actual or virtual entity that principles, in order for biorepository to have good may receive, process, store or distribute biological quality specimens to begin with. Biorepository will specimens, and their associated data as appropriate, provide active specimen-tracking system for storage in support of a study or multiple studies. As the idea and distribution purposes. Various softwares for of biorepository is already familiar to its research specimen management system are available, such as practices, it is only natural that the NIHRD should FreezerworksTM, Laboratory Data Management proceed to set up an actual facility for biorepository to anticipate genetic and biomolecular era of Management System (LIMS), etc. research in Indonesia. Informed consent is another critical topic in Originally, biorepository service is not intended for biorepository service. The Declaration of Helsinky short term run. The US Department of Defense and ISBER Guideline (2012) require that the Serum Repository in Silver Spring, Maryland has collection, storage, and use of human specimens and samples stored from the HIV screening program back associated data should be conducted in a way that in 1985. John Hopkins Biological Repository (JHBR), respects the individual and maintains privacy and which was established in 1984, currently consists of confidentiality. Biorepositories should also adhere to 1,500 square feet of biosafety level 2 laboratories on and be kept up-to-date on relevant national human the Johns Hopkins Bloomberg School of Public Health subjects regulations, privacy regulations, and other (JHSPH) with additional 6,000 square feet in facility relevant national, state, and local laws. Subjects located 3 miles away from JHSPH, capable of holding should have an informed choice about whether to 60 liquid nitrogen vapor phase cryogenic units. Nevertheless, a prototype model of biorepository service can still be started with as many as one freezer available in the existing laboratory for short-term storage. Such case may apply to a simple population-based collection model, i.e. biorepository that stores specimens obtained for defined study purposes. Further development should foresee future needs, allowing it to expand its capacity in line with the growing number of specimens it holds. Because ensuring specimen quality for future research and managing the specimens are its priority, regular preventive maintenance program, backups, Page 5 of 6
Newsletter Issue #18, March 2015

provide specimens and data to the repository and research, especially researches to discover new drugs, agree, where applicable, to future research use. The new vaccines, or new diagnostic tools. Stored consent may be obtained for a specific research specimens can be retrieved, with respect to subject's project, i.e. details of the project specifically consent, privacy and confidentiality, for testing the outlined, or for unspecified future research providing new intervention prior to the actual test on human. general information about the possible future Moreover, retrieval of stored specimens will save much time and resources as the investigator will not repeat specimen collection phase, particularly if the With all that crucial points in mind, setting up a subject of interest belongs to vulnerable group or biorepository may not seem to be an easy task. subpopulation. The benefit of having a biorepository However, the NIHRD will stay committed, and the facility will outshine the vast investment made. development of a biorepository facility is already listed in its plan. The NIHRD realizes the value of biorepository as a crucial bridge for many areas of by dr. Retna Mustika Indah. commemorate the world TB Day on March 24, we have trivia questions about TB drugs for you. The This diaryquinolines, hopefully, can bring a new hope in treating MDR TB. What is the questions are really easy, and you can definitely answer them if you read our newsletters. So here you name of the drug? 3. This new drug from nitroimidazole group inhibits the synthesis of mycobacterial 1. Together with INH, this drug is used as proteins and lipids but not nucleic acids. The standard regimen in treatment of drug cocktail of this drug with moxifloxacin and sensitive TB patients on continuation phase. pyrazinamide has potency to cure drug This drug intensely red solid, and the small sensitive TB and MDR TB. What is the name fraction which reaches body fluids is known for imparting a harmless red-orange color to Please email your answer to the urine. What is the name of the drug? by March 27 for a chance to win a souvenir! 2. Approved by FDA in December 2012, this drug becomes the first new drug with novel mechanism in over 40 years. : dr. M. Karyana, dr. Herman Kosasih INA-RESPOND
: dr. Anandika Pawitri Newsletter
: Dedy Hidayat S, S.Kom : Agus Dwi Harso, Dona Arlinda, dr. M. Karyana dr. Retna Mustika : INA-RESPOND Network and Partners : All Copyright and trademark are recognized
We would like to hear from you. Go ahead and send us your scientific articles, team profile, or feedback about the newsletter to [email protected] Page 6 of 6

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