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RDBPCT for Black Seed Supplementation in Asthma: Methodology Development Abdulrahman Koshak PharmD, MSc, PhD candidate UCL School of Pharmacy, London Faculty of Pharmacy, King Abdulaziz University, Jeddah الحديث عن أيب هريرة رضي هللا عنه أنه مسع رسول هللا صلى هللا عليه وسلم يقول ( في الحبة السوداء شف اء من كل داء إال السام ) متفق عليه Black Seed (Nigella sativa) • Distinguished historical and religious focus • Arabic, Unani, Ayurvedic, and Chinese medicine – In bible: the curative black cumin – In Isaiah, mentioned in Hebrew word “Ketsah” – In Islam, mentioned by prophet as a cure for all diseases except death Chemical Composition Fixed oils 40% Alkaloids Volatile oils 1.6% BS Saponins Other Active Compound Thymoquinone Randomised Double-Blind PlaceboControlled Clinical Trial (RDBPCT) Method development 1st Step: Literature Review • Searching medical databases such as (PubMed, EMBASE, google scholar) for an evidence of black seed benefits in bronchial asthma • 15 pre-clinical studies found a positive effect of Black seed or TQ in different cellular and animal models of asthma. • 4 preliminary clinical trials reported its possible effectiveness in asthma (water extract, powdered, oil) 2nd Step: Research Team Formation • Specialist medical doctor/s • Medical statistician • Pharmaceutical (pharmacognosy) 3rd step: Trial design 3.1. Resources Guide for Study Protocol • Guidelines: – European Medicines Agency's scientific guidelines 2013 on clinical investigation of medicinal products for treatment of asthma • Journal articles: – Adcock IM, Caramori G, Chung KF. New targets for drug development in asthma. Lancet 2008;372:1073–87. doi:10.1016/S0140-6736(08)61449-X – Szefler SJ, Wenzel S, Brown R, et al. Asthma outcomes: biomarkers. J Allergy Clin Immunol 2012;129:S9–23. doi:10.1016/j.jaci.2011.12.979 • Textbooks: – Hansel TT, Barnes PJ (eds): New Drugs and Targets for Asthma and COPD. Prog Respir Res. Basel, Karger 2010, vol 39, pp 3–23 • Research team recommendations 3.2 Sample Size • Sample size is estimated based on the primary endpoint (Asthma Control Test “ACT”) • nQuery Advisor software Research Type • Prospective, double-blind, placebocontrolled, randomised clinical intervention study of Nigella sativa oil supplementation DBPC-RCT • Phase II clinical trial Inclusion Criteria • Adult male/female (age 18-65 years) • Partially controlled and Uncontrolled asthmatic patient based on GINA guidelines (ACT score 5-20) • No severe asthma exacerbation in the last 4 weeks • Able to obtain consent Exclusion Criteria • Co-morbid serious conditions such as; cancer, renal, hepatic, cardio-vascular, gastrointestinal diseases, mental health conditions and respiratory disorder such as TB and COPD. • Smoking history • Pregnant women • Known history of hypersensitivity to Black seed. • Taking Black seed or medications that interact with it: Anticoagulant/Antiplatelet, Antidiabetic, Antihypertensive, CNS depressants, and Immunosuppressant drugs. Step 4: Ethical approval & registration • • • • • UCL ethics (6419/002) KAU ethical committee (95-15) Saudi FDA Ministry of Health www.clinicaltrials.gov (NCT02407262) Title: Potential Benefits of Nigella sativa Oil Supplementation on Asthma Inflammation and Outcome SFDA Requirements Step 5: Arrangements for Study Locations • Medical outpatient clinics at KAUH • Private allergy clinic at KAUH and Sameer Abbas medical centre • Primary care centres at MOH Step 6: determination and preparation of the study product Which Black seed? Quality Study of Black Seed (Metabolomic method) Variability of Black Seed (Nigella sativa L.) samples from Different Origins: Using NMR analytical tool Score plot of 23 black seed samples Score Plot of 6 Oil Products Thyomoquinone Analysis (HPLC) TQ Conc. (W/W) % 3 2.5 2 1.5 1 0.5 0 Sample Sample Sample Sample Sample Sample Sample Sample 1 2 3 4 5 7 9 10 Anti-inflammatory (in-vitro) Analysis Effect of Black seed extracts on T-cells inflammatory mediators Effect of Black seed extracts on T-cells inflammatory mediators Effect of Black seed extracts on A549 cells’ inflammatory mediator Effect of Black seed extracts on A549 cells’ inflammatory mediator Effect of Black seed extracts on signalling pathways in A549 cells Study Product and Placebo • Marnys® Cuminmar (Nigella sativa oil, 500mg) SFDA licensed. • Placebo (olive oil) • Dose: one capsules (500 mg) twice daily (total 1 g/day) for 4 weeks. Step 7: Randomisation and Blinding • An external medical scientist created block randomisation table using the website (https://www.sealedenvelope.com) with block sizes of 2,4 for 100 sample size. • A list of unique codes has been generated for each box of trial medications (both treatment and placebo) Step 8: Outcomes measurement arrangements • Asthma Control Test • lung function (PFT) (ACT) Step 8: Outcomes measurement arrangements • Complete blood count (CBC) • Serum biomarkers (Total Immunoglobulins, Inflammatory mediators such as: Cytokines, chemokines, cell singling proteins) Conclusions • In order to design the methodology of a RDBPCT of black seed in asthma, at least eight developmental steps were implemented. • This work may provide a guidance for steps to conduct a RDBPCT on herbal medicines in the context of saudi healthcare system. Acknowledgment Prof Emad Koshak Prof Siraj Wali Prof Omar AlAmoudi Dr Abdulrahman Demerdash Dr Majdi Qotob Dr Peter Pushparaj Dr Li Wei Prof Michael Heinrich • Immunology lab at KAUH and KFMRC • Medical residents, nurses, and staff References • • • • • • • Ahmad, A. et al., (2013). A review on therapeutic potential of Nigella sativa: A miracle herb. Asian Pacific Journal of Tropical Biomedicine, 3(5), pp.337–352. Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3642442&tool=pmcentrez&rende rtype=abstract [Accessed March 20, 2013]. Ali, M.A. et al., (2012). CHARACTERISTICS OF OILS AND NUTRIENT CONTENTS OF NIGELLA SATIVA LINN. AND TRIGONELLA FOENUM-GRAECUM SEEDS. Chenmical Society of Ethiopia, 26(1), pp.55–64. Booker, A. et al., (2011). Metabolomic profiling of saw palmetto products using proton-NMR spectroscopy and multi-variate analysis. Planta Medica, 77(12), p.1249. Available at: https://www.thieme-connect.de/DOI/DOI?10.1055/s-0031-1282148 [Accessed July 30, 2013]. Botnick, I. et al., (2012). Distribution of primary and specialized metabolites in Nigella sativa seeds, a spice with vast traditional and historical uses. Molecules, 17(9), pp.10159–77. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22922285 [Accessed March 16, 2013]. Datta, A.K. et al., (2012). BLACK CUMIN (NIGELLA SATIVA L.) – A REVIEW. Journal of Plant Development Sciences, 4(1), pp.1–43. Fidele, T., Piater, L. & Dubery, I., (2013). Plant metabolomics: A new frontier in phytochemical analysis. South African Journal of Science, 109(5/6), p.11. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23107118 [Accessed March 6, 2013]. * NaturalMedicines, 2014. Black Seed Monograph. Available at: Refrences • • • • • • • Khare, C.P., (2004). Encyclopedia of Indian Medicinal Plants: Rational Western Therapy, Ayurvedic and Other Traditional Usage, Botany, Springer Verlag. Available at: http://books.google.co.uk/books?id=mz_RAAAACAAJ. Kim, H.K., Choi, Y.H. & Verpoorte, R., (2010). NMR-based metabolomic analysis of plants. Nature protocols, 5(3), pp.536–49. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20203669 [Accessed May 27, 2013]. Liu, X., Abd El-aty, A.M. & Shim, J., (2011). Various Extraction and Analytical Techniques for Isolation and Identification of Secondary Metabolites from Nigella sativa Seeds. Mini-Reviews in Medicinal Chemistry, 11, pp.947–955. Michel, C.G. et al., (2011). Phytochemical and biological investigation of the extracts of Nigella sativa L. seed waste. Drug testing and analysis, 3(4), pp.245–54. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21309000 [Accessed May 15, 2013]. Nickavar, B. et al., (2003). Chemical composition of the fixed and volatile oils of Nigella sativa L. from Iran. Zeitschrift für Naturforschung, 58(9-10), pp.629–31. Available at: http://www.ncbi.nlm.nih.gov/pubmed/14577620. Okazaki, Y. & Saito, K., (2012). Recent advances of metabolomics in plant biotechnology. Plant biotechnology reports, 6(1), pp.1–15. Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3262138&tool=pmcentrez&re ndertype=abstract [Accessed April 8, 2013]. Trevor, J.L. & Deshane, J.S., 2014. Refractory asthma: mechanisms, targets, and وهو في الصحيحين وغيرهما ،ولفظه عند البخاري عن خالد بن سعد قال :عليكم بهذه الحبيبة السوداء ،فخذوا منها خمسا ً أو سبعا ً فاسحقوها ثم اقطروها في أنفه بقطرات زيت في هذا الجانب وفي هذا الجانب ،فإن عائشة حدثتني أنها سمعت رسول هللا صلى هللا عليه وسلم يقول :إن هذه الحبة السوداء شفاء من كل داء إال من السام ،قلت :وما السام، قال :الموت.