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Introduction:The past few months have been an invaluable experience for me as I completed my medical doctor internship. This internship provided me with the opportunity to apply the theoretical knowledge I acquired during my medical school years to real-life clinical scenarios. Through this internship, I gained a deeper understanding of the medical field, honed my clinical skills, and developed a sense of empathy towards patients. This summary aims to reflect on the key learnings and experiences during my internship.1. Clinical Skills Development:One of the primary goals of my internship was to enhance my clinical skills. I had the chance to observe and assist in various medical procedures, including patient examinations, diagnostic tests, and treatments. Under the guidance of experienced physicians, I learned the importance of a thorough patient history, physical examination, and diagnostic interpretation. I also gained proficiency in basic life support, which proved to be a crucial skill during emergency situations.2. Understanding Patient Care:The internship emphasized the importance of patient care, not just in terms of medical treatment but also in terms of empathy, communication, and support. I encountered patients from diverse backgrounds, each with unique needs and concerns. This experience taught me to approach each patient with compassion, actively listen to their concerns, and tailor my care accordingly. I learned that effective communication and empathy are essential in building trust and ensuring patient satisfaction.3. Professionalism and Ethics:The internship emphasized the significance of professionalism and ethics in the medical field. I was trained to adhere to hospital policies and guidelines, maintain patient confidentiality, and respect the dignity of every individual. I also learned about the ethical considerations involved in medical decision-making, such as informed consent, patient autonomy, and end-of-life care.4. Teamwork and Collaboration:Working in a hospital environment highlighted the importance of teamwork and collaboration among healthcare professionals. I had the opportunity to work alongside nurses, pharmacists, and other physicians, learning to coordinate care and communicate effectively with them. This experience helped me appreciate the multidisciplinary approach to patient care and the importance of each team member's role in providing comprehensive healthcare.5. Learning from Mistakes:During my internship, I encountered situations where my initial assessments or treatments were not entirely accurate. These experiences taught me the importance of learning from mistakes and seeking guidance when needed. I learned to analyze the reasons behind my errors, reflect on my actions, and strive for continuous improvement in my clinical practice.6. Personal Growth:Apart from the technical and clinical aspects, the internship also contributed to my personal growth. I developed resilience, adaptability, and time management skills. I learned to prioritize tasks, manage stress, and maintain a balance between work and personal life.Conclusion:In conclusion, my medical doctor internship was a transformative experience that enriched my understanding of the medical field. I am grateful for the opportunities and challenges that came my way duringthis period. This internship has not only prepared me for my future career as a physician but has also shaped me into a more compassionate, empathetic, and skilled healthcare professional. I look forward to applying the knowledge and skills I gained during this internship as I continue my journey in medicine.。
英语版实验报告范文Alright, here's a sample of an experimental report written in an informal and conversational English style, while maintaining paragraph independence and avoiding connective words or transitions:---。
So, I was messing around in the lab today, trying out this new experiment. It's kind of crazy, but I think it might work. You know, when you mix these two chemicals together, they usually explode or something, but I've been trying to find the right ratio to make it react differently.And guess what? It worked! I don't know how, but it did. The colors were amazing. They swirled and changed, almost like a mini fireworks display in my test tube. I was so surprised I almost dropped it.After that, I had to record all the data, of course.Numbers and stuff. But you know what? It was actually fun.I mean, I get to be a scientist for a day, mixing chemicals and seeing what happens. It's like playing with science toys or something.Then I had to write up my observations. That was a bit boring, but it's important to be thorough, right? I described everything I saw, even the little details that might not seem important at first. You never know what could be a key clue.And finally, I had to think about what it all means. You know, why did it work? What made the chemicals react like that?。
Abstract:This study aimed to evaluate the efficacy and safety of a newantipyretic drug in children with acute febrile illness. A total of 100 children aged 6 months to 12 years with fever were randomly assigned to either the treatment group (n=50) receiving the new antipyretic drug or the control group (n=50) receiving a standard antipyretic medication. The primary outcome measure was the time to achieve a reduction in body temperature to normal levels. Secondary outcomes included the duration of fever, adverse events, and parental satisfaction. The results showed that the new antipyretic drug was significantly more effective than the standard medication in reducing body temperature and缩短发热持续时间，with no significant difference in adverse events between the two groups. The study concludes that the new antipyretic drug is a safe andeffective treatment option for children with acute febrile illness.Keywords: Antipyretic drug, children, fever, efficacy, safety, acute febrile illnessIntroduction:Acute febrile illness is a common condition in children, often caused by infections such as viral or bacterial infections. Fever is a common symptom of these illnesses and can be distressing for both children and their parents. Effective antipyretic therapy is crucial for managing fever and reducing the discomfort associated with acute febrile illness. The current standard of care for fever management in children is the use of nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen or acetaminophen. However, there is a need for new antipyretic drugs with improved efficacy and safety profiles. This study aimed to evaluate the efficacy and safety of a new antipyretic drug in children with acute febrile illness.Materials and Methods:Study Design:This was a randomized, double-blind, parallel-group clinical trial.Participants:A total of 100 children aged 6 months to 12 years with a diagnosis of acute febrile illness were enrolled in the study. Inclusion criteria were: age between 6 months and 12 years, body t emperature ≥38.0°C (100.4°F), and presence of fever for less than 48 hours. Exclusion criteria were: known contraindications to the study medications, chronic diseases that could cause fever, and a history of severe adverse reactions to antipyretic drugs.Randomization:Participants were randomly assigned to either the treatment group (n=50) or the control group (n=50) using a computer-generated randomizationlist. The study medications were identical in appearance and packaging, and the researchers were blinded to the group assignment.Interventions:The treatment group received the new antipyretic drug (10 mg/kg orally every 6 hours as needed), while the control group received a standard antipyretic medication (10 mg/kg ibuprofen suspension orally every 6 hours as needed).Outcome Measures:The primary outcome measure was the time to achieve a reduction in body temperature to normal levels (≤37.5°C or 99.5°F). Secondary outcomes included the duration of fever, incidence of adverse events, andparental satisfaction assessed using a standardized questionnaire.Statistical Analysis:Data were analyzed using the Statistical Package for the Social Sciences (SPSS) software. The primary analysis was an intention-to-treat analysis. The efficacy of the new antipyretic drug was assessed using the time to achieve normal body temperature. The duration of fever was compared between groups using the Mann-Whitney U test. Incidence of adverseevents was analyzed using Fisher's exact test. Parental satisfaction was compared using the Chi-square test.Results:A total of 100 children were enrolled in the study, with 50 in the treatment group and 50 in the control group. The mean age of the participants was 7.5 years (range 6-12 years). The mean time to achieve normal body temperature was significantly shorter in the treatment group (3.5 hours) compared to the control group (5.2 hours) (p<0.05). The duration of fever was also significantly shorter in the treatment group (24 hours) compared to the control group (36 hours) (p<0.05). There were no significant differences in the incidence of adverse events between the two groups (p>0.05). Parental satisfaction with the new antipyretic drug was higher than with the standard medication (p<0.05).Discussion:This study demonstrated that the new antipyretic drug was significantly more effective than the standard medication in reducing body temperature and缩短发热持续时间 in children with acute febrile illness. The new drug was well tolerated, with no significant differences in adverse events between the treatment and control groups. These findings suggest that the new antipyretic drug could be a valuable addition to the treatment options available for children with acute febrile illness.Conclusion:The new antipyretic drug is a safe and effective treatment option for children with acute febrile illness, offering a faster reduction in body temperature and shorter duration of fever compared to standard antipyretic medications. Further research is needed to evaluate thelong-term effects and cost-effectiveness of this new drug.References:- American Academy of Pediatrics. (2011). Febrile seizures. Pediatrics, 127(3), e726-e735.- Thacker SB, Cherry JD, Poehling KA, et al. (2008). The burden of childhood febrile seizures in the United States. Pediatrics, 121(6),e1487-e1494.- Blumer JL, Flanagan EP, Towner K, et al. (2012). Ibuprofen vs acetaminophen for the treatment of fever in children with acute infections: a randomized controlled trial. JAMA, 308(14), 1453-1461.Appendices:- Informed Consent Form- Participant Demographics- Study Medication Dosing Schedule- Adverse Event Reporting Form- Parental Satisfaction Questionnaire。
药物临床试验的工作总结英文回答：Summary of Clinical Drug Trial.Introduction.A clinical drug trial is a research study that evaluates the safety and effectiveness of a new drug or treatment. It is conducted in phases, with each phase designed to collect specific data about the drug.Phase 1。
Phase 1 trials are the first studies to test a drug in humans. They are usually small, with a few dozen participants. The primary goal of Phase 1 trials is to determine the drug's safety and tolerability.Phase 2。
Phase 2 trials are larger than Phase 1 trials, with typically hundreds of participants. They are designed to evaluate the drug's effectiveness for a specific condition.Phase 3。
Phase 3 trials are the largest and most comprehensive phase of clinical drug trials. They are designed to confirm the drug's effectiveness and safety in a large population of patients.Phase 4。
Title: Efficacy and Safety of a Novel Antidepressant in Major Depressive DisorderIntroduction:Major depressive disorder (MDD) is a common mental health condition characterized by persistent feelings of sadness, loss of interest, and decreased energy. Current treatments for MDD include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptakeinhibitors (SNRIs), and tricyclic antidepressants (TCAs). However, some patients may not respond adequately to these treatments or experience adverse effects. This clinical trial aimed to evaluate the efficacy and safety of a novel antidepressant, known as NovelAntidepressant (NA), in the treatment of MDD.Methods:The study was a randomized, double-blind, placebo-controlled trial conducted at three academic medical centers in the United States. Participants were diagnosed with MDD according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria. Inclusion criteria were age 18-65 years, a minimum Hamilton Depression Rating Scale (HDRS) score of 17, and a history of inadequate response to at least one antidepressant treatment. Exclusion criteria included pregnancy, active substance abuse, and contraindications to the study medication.A total of 120 participants were randomly assigned to one of four treatment groups: Group A (NA 50 mg/day), GroupB (NA 100 mg/day), GroupC (NA 150 mg/day), and GroupD (placebo). Participants were treated for12 weeks, with follow-up assessments at weeks 2, 4, 6, 8, 10, and 12. The primary outcome measure was the change in HDRS score from baseline to week 12. Secondary outcome measures included the Montgomery-Asberg Depression Rating Scale (MADRS), the Sheehan Disability Scale (SDS), and the Patient Global Impression of Change (PGIC).Results:A total of 113 participants completed the study. The mean age of the participants was 38.2 ± 11.7 years, and 57.5% were female. There were no significant differences in demographic or clinical characteristics between the treatment groups at baseline.At week 12, the HDRS score improved significantly in all treatment groups compared to the placebo group (p < 0.001). The mean HDRS score change from baseline to week 12 was as follows: Group A (-14.2 ± 6.1), Group B (-15.8 ± 5.9), Group C (-16.5 ± 5.7), and Group D (-6.2 ±6.5). The between-group differences in HDRS score change were not statistically significant.Similarly, the MADRS and SDS scores also improved significantly in all treatment groups compared to the placebo group (p < 0.001). The mean change in MADRS score from baseline to week 12 was as follows: Group A (-10.5 ± 4.2), Group B (-11.8 ± 3.9), Group C (-12.2 ± 3.7), and Group D (-4.8 ± 4.5). The mean change in SDS score from baseline to week 12 was as follows: Group A (-8.3 ± 3.2), Group B (-9.1 ± 2.8), Group C (-9.8 ± 2.6), and Group D (-3.4 ± 3.1).The PGIC showed a significant improvement in all treatment groups compared to the placebo group (p < 0.001). The percentage ofparticipants with a "much improved" or "very much improved" rating was as follows: Group A (75%), Group B (80%), Group C (85%), and Group D (45%).Regarding safety, the most common adverse events reported were headache, nausea, and dry mouth. These adverse events were generally mild to moderate in severity and did not lead to discontinuation of the study medication in any of the treatment groups.Conclusion:The results of this clinical trial indicate that the novel antidepressant, NA, is effective and safe in the treatment of MDD. NA demonstrated significant improvements in HDRS, MADRS, and SDS scores, as well as PGIC, compared to placebo. The adverse event profile was consistent with the known side effects of SSRIs and SNRIs. Furtherresearch is needed to confirm the long-term efficacy and safety of NA in the treatment of MDD.Keywords: Major depressive disorder, NovelAntidepressant, efficacy, safety, randomized controlled trial, HDRS, MADRS, SDS, PGIC.。
Abstract:The rapid spread of viral infections has posed significant challenges to global public health. In this study, we evaluated the efficacy of a novel antiviral drug, AV-123, against a panel of viral strains in vitro. The drug was tested on various cell lines, and its inhibitory effects were measured using the viral plaque assay and quantitative real-time PCR. The results demonstrated that AV-123 exhibited potent antiviral activity against the tested viruses, with minimal cytotoxicity. This study provides a foundation for further investigation of AV-123 as a potential therapeutic agent against viral infections.Introduction:Viral infections are a major cause of morbidity and mortality worldwide. The emergence of drug-resistant strains has further complicated the management of these infections. Antiviral drugs are essential in controlling viral diseases, but their development has been limited by the rapid evolution of viral pathogens. In this context, the identification of novel antiviral agents is crucial. This study aimed to evaluate the efficacy of a newly synthesized antiviral drug, AV-123, against various viral strains in vitro.Materials and Methods:1. Cell Lines and Viruses:The following cell lines were used in this study: HEp-2 (human epidermoid carcinoma), Vero (African green monkey kidney), and MDCK (Madin-Darby canine kidney). The viruses used were: Influenza A virus (H1N1), Human papillomavirus (HPV-16), and Human immunodeficiency virus (HIV-1).2. Drug Preparation:AV-123 was synthesized in the laboratory and characterized by nuclear magnetic resonance (NMR) and mass spectrometry (MS). The drug was dissolved in dimethyl sulfoxide (DMSO) and diluted to various concentrations for the experiments.3. Viral Inoculation and Drug Treatment:Cells were seeded in 96-well plates and allowed to adhere for 24 hours. The virus was added to the cells, and the mixture was incubated for 1 hour at 37°C. After removal of the virus, cells were treated with various concentrations of AV-123 for 48 hours.4. Viral Plaque Assay:The antiviral activity of AV-123 was assessed using the viral plaque assay. Briefly, cells were infected with the virus and treated with AV-123. After incubation, the virus was neutralized, and the cells were overlayed with a semi-solid agarose medium containing dye. The plaques were counted after 24 hours of incubation.5. Quantitative Real-Time PCR:The efficacy of AV-123 was also evaluated using quantitative real-time PCR. Total RNA was extracted from the infected cells, and viral RNA was amplified using specific primers. The cycle threshold (Ct) values were used to determine the inhibitory activity of the drug.6. Cytotoxicity Assays:The cytotoxicity of AV-123 was determined using the MTT assay. Cells were treated with various concentrations of the drug, and the absorbance at 570 nm was measured to assess cell viability.Results:1. Antiviral Activity:AV-123 showed potent antiviral activity against the tested viruses. The EC50 values for Influenza A virus, HPV-16, and HIV-1 were 0.5 μM, 1.0 μM, and 1.5 μM, respectively. The drug effectively reduced the viral titer in the cell culture, as evidenced by the decreased number of plaques and Ct values.2. Cytotoxicity:The cytotoxicity of AV-123 was minimal at the concentrations used inthis study. The IC50 values for HEp-2, Vero, and MDCK cells were >10 μM, indicating that the drug is safe for use at therapeutic levels.3. Mechanism of Action:Further studies are required to elucidate the mechanism of action of AV-123. However, preliminary results suggest that the drug may inhibitviral entry and replication by interfering with viral surface proteins and enzymes.Discussion:The results of this study demonstrate that AV-123 is a potent antiviral agent against various viral strains. The drug exhibits minimal cytotoxicity, making it a promising candidate for further development as a therapeutic agent. Further research is needed to optimize the drug's formulation, assess its efficacy in vivo, and investigate its potential side effects.Conclusion:In conclusion, the novel antiviral drug AV-123 showed significantantiviral activity against influenza A virus, HPV-16, and HIV-1 in vitro. The drug's minimal cytotoxicity suggests its potential as a therapeutic agent. Further investigation is warranted to assess the drug's efficacyin vivo and refine its clinical application.References:1. Y. Wang, Z. Liu, H. Li, et al. "Antiviral activity of a novel acyclic guanidine derivative against human immunodeficiency virus type 1." Antiviral Research, 138 (2016): 29-35.2. S. P. Brown, A. R. Jones, and A. M. Saphire. "Structure and function of the human papillomavirus type 16 L1 capsid." Journal of Virology, 82 (2008): 7154-7162.3. T. C. Quinn, and D. R. Russell. "Antiviral agents for influenza." Current Opinion in Pharmacology, 11 (2011): 706-712.4. P. A. Tijms, J. C. de Vries, and R. A. M. Fouchier. "Influenza A virus resistance to neuraminidase inhibitors." Current Opinion in Virology, 4 (2014): 53-59.5. S. L. Brown, S. R. Gamble, and R. M. Bertholet. "Efficacy and safety of antiviral agents for the treatment of human papillomavirus infection." Expert Review of Anti-Infective Therapy, 15 (2017): 559-568.。
英文实验报告Experimental Report。
Introduction。
The purpose of this experiment was to investigate the effects of different temperatures on the rate of enzyme activity. Enzymes are biological catalysts that speed up chemical reactions in living organisms. They are sensitive to changes in temperature, and this experiment aimed to explore how temperature affects the activity of the enzyme catalase.Materials and Methods。
To conduct this experiment, a solution of hydrogen peroxide was prepared and divided into several test tubes. Each test tube was then placed in a water bath at a specific temperature (5°C, 25°C, 45°C, and 65°C). A small piece of liver was added to each test tube, and the rate of oxygen production was measured using a gas syringe.Results。
The results of the experiment showed that the rate of enzyme activity increased as the temperature rose from 5°C to 45°C. However, at 65°C, the enzyme activity decreased significantly, and the reaction rate slowed down. This indicates that there is an optimal temperature for enzyme activity, and beyond this point, the enzyme becomes denatured and loses its function.Discussion。
英文版实验报告英文版实验报告Introduction:In this report, we present the findings and analysis from a recent experiment conducted to investigate the effects of caffeine on cognitive performance. Caffeine, a widely consumed psychoactive substance, is known to have stimulant effects on the central nervous system. The objective of this experiment was to examine whether caffeine could enhance cognitive abilities such as attention, memory, and reaction time.Methodology:Participants: A total of 50 healthy adult volunteers aged between 18 and 30 years were recruited for the study. They were randomly assigned to two groups: the experimental group (received caffeine) and the control group (received a placebo).Procedure: Participants arrived at the laboratory after an overnight fast and were instructed to abstain from consuming any caffeinated beverages or food for at least 12 hours prior to the experiment. They were then given either a capsule containing 200mg of caffeine or a placebo capsule. The experimenters, as well as the participants, were blinded to the group assignments.Cognitive tests: After a 30-minute absorption period, participants completed a battery of cognitive tests. These included a sustained attention task, a memory recall task, and a reaction time test. The tests were designed to measuredifferent aspects of cognitive function.Results:The results of the experiment revealed interesting insights into the effects of caffeine on cognitive performance. Participants in the experimental group, who received caffeine, demonstrated significantly better performance on the sustained attention task compared to those in the control group. They also exhibited improved memory recall and faster reaction times.Discussion:The findings of this experiment support the hypothesis that caffeine can enhance cognitive abilities. The stimulant properties of caffeine may have contributed to the improved attention and memory performance observed in the experimental group. The faster reaction times may be attributed to the increased alertness and arousal associated with caffeine consumption.These results are consistent with previous research on the effects of caffeine on cognitive function. Caffeine has been shown to increase alertness, improve attention, and enhance memory in various studies. However, it is important to note that individual responses to caffeine can vary, and some individuals may experience negative effects such as increased anxiety or disrupted sleep. Implications:The findings of this experiment have implications for various fields, including education, workplace productivity, and even sports performance. The use of caffeine as a cognitive enhancer may be beneficial in situations that requiresustained attention and mental alertness, such as during exams or high-pressure tasks.However, it is crucial to consider the potential risks and limitations associated with caffeine consumption. Excessive intake of caffeine can lead to adverse effects such as jitteriness, increased heart rate, and disrupted sleep patterns. Therefore, it is recommended to consume caffeine in moderation and be aware of individual tolerance levels.Conclusion:In conclusion, this experiment provides evidence that caffeine can enhance cognitive performance, particularly in the domains of attention, memory, and reaction time. The findings support the use of caffeine as a cognitive enhancer, but caution should be exercised regarding its potential side effects. Further research is needed to explore the long-term effects of caffeine on cognitive function and to identify optimal dosages for different populations.。
临床试验总结报告撰写英文回答：Writing a summary report for a clinical trial can be a challenging task as it requires presenting the findings and conclusions of the study in a clear and concise manner. In this report, I will provide a comprehensive summary of the clinical trial I conducted, highlighting the key results and implications.To begin with, the clinical trial aimed to investigate the efficacy and safety of a new drug for the treatment of hypertension. The study design involved a randomized controlled trial with two groups: the experimental group receiving the new drug and the control group receiving a placebo. The trial lasted for six months and included a sample size of 500 participants.The results of the trial demonstrated a significant reduction in blood pressure levels among the participantsin the experimental group compared to the control group. This finding suggests that the new drug is effective in lowering blood pressure and could be a promising treatment option for patients with hypertension.Furthermore, the trial also assessed the safety profile of the new drug. Adverse events were monitored throughout the study period, and it was found that the incidence of adverse events was comparable between the experimental and control groups. This indicates that the new drug is well-tolerated and has a favorable safety profile.In addition to the quantitative results, qualitative feedback from the participants was also collected. Many participants reported improvements in their overall well-being and quality of life after taking the new drug. This subjective feedback further supports the positive impact of the new drug on hypertension management.Based on the findings of this clinical trial, it can be concluded that the new drug is both effective and safe for the treatment of hypertension. These results have importantimplications for healthcare professionals and patients alike, as they provide evidence for the use of this drug in clinical practice.中文回答：临床试验总结报告的撰写是一项具有挑战性的任务，因为它要求以清晰简洁的方式呈现研究的结果和结论。
Title:[Experiment Name]Date of Experiment:[Date]Objective:To [state the main objective of the experiment].Materials:- [List all materials used in the experiment, including equipment, chemicals, and any other necessary items.]Procedure:1. [Step 1 of the procedure]2. [Step 2 of the procedure]3. [Step 3 of the procedure]...[Continue listing all steps in the procedure.]Data Collection:- [Description of how data was collected, including measurements, observations, and any other relevant information.]Data Analysis:- [Summary of the data analysis techniques used, such as calculations, graphs, or statistical tests.]Results:- [Present the results of the experiment in a clear and concise manner. Include tables, graphs, or charts as necessary.]Discussion:- [Interpret the results and discuss their significance. Compare the results to expected outcomes or previous studies. Address any anomalies or unexpected results.]- Anomaly 1:- [Description of the anomaly]- [Possible reasons for the anomaly]- [Impact on the experiment and conclusions]- Anomaly 2:- [Description of the anomaly]- [Possible reasons for the anomaly]- [Impact on the experiment and conclusions]- [Continue with any additional anomalies or interesting observations.]Conclusion:- [Summarize the main findings of the experiment and their implications. Restate the objective and whether it was achieved.]Recommendations:- [Suggest any improvements or modifications to the experiment procedure or equipment. Propose further studies or applications of the findings.]References:- [List all sources cited in the report, including textbooks, journal articles, and online resources.]Appendix:- [Include any additional information, such as detailed data tables, raw data, or additional figures that support the findings of the experiment.]---Example:Title:Investigation of the Effect of Temperature on the Rate of PhotosynthesisDate of Experiment:March 15, 2023Objective:To determine the effect of varying temperatures on the rate of photosynthesis in spinach leaves.Materials:- Spinach leaves- Light source- Beakers- Thermometer- Stopwatch- Sodium bicarbonate solution- pH test strips- Distilled waterProcedure:1. Prepared spinach leaves by removing stems and rinsing them under tap water.2. Placed equal amounts of spinach leaves in each beaker.3. Prepared a sodium bicarbonate solution with varying concentrations.4. Divided the beakers into groups, each with a different temperature(e.g., 10°C, 20°C, 30°C, 40°C).5. Submerged the leaves in the respective solutions and measured the pH using pH test strips.6. Taped a light source above each beaker and recorded the time it took for the pH to increase by 1 unit.7. Repeated the experiment three times to ensure accuracy.Data Collection:- pH increase over time for each temperature group.Data Analysis:- Calculated the average time for pH increase for each temperature group.Results:- [Insert table or graph showing the average time for pH increase at each temperature.]Discussion:- The data shows that the rate of photosynthesis increases with temperature up to a certain point, after which it begins to decrease. This is consistent with the hypothesis that temperature affects the rate of enzyme activity in photosynthesis.- At lower temperatures (10°C and 20°C), the rate of photosynthesis was significantly slower, indicating the importance of optimal temperature for enzyme activity.- At higher temperatures (30°C and 40°C), the rate of photosynthesis increased but then decreased, suggesting a possible denaturation of enzymes at very high temperatures.Conclusion:The experiment confirmed that temperature significantly affects the rate of photosynthesis in spinach leaves. The optimal temperature for photosynth esis in this study was found to be around 30°C.Recommendations:- Further studies should investigate the specific temperature rangesthat are optimal for photosynthesis in different plant species.- The experiment could be modified to include more temperature groups and a wider range of temperatures to observe the exact point of enzyme denaturation.References:- [List of references used in the report.]Appendix:- [Include any additional information, such as detailed data tables, raw data, or additional figures.]。
Reviewer: Cynthia A. Rask, M.D.Through: Marc K. Walton, M.D., Ph.D.Karen Weiss, M.D.Date: 23 January 2002Biologics License Application SupplementMedical Officer’s ReviewRebif® (Interferon β-1a)FOR TREATMENT OFRELAPSING-REMITTING MULTIPLE SCLEROSISSubmitted by Serono, Inc.STN #: 103780 / 0TABLE OF CONTENTS OVERVIEW (4)Scope of this revie w (4)Abbreviations and Definitions of Terms Used in This Review (5)INTRODUCTION (7)Multiple Sclerosis (7)Background and Diagnostic Criteria (7)Current Treatment of MS (8)The Orphan Drug Act and Orphan Drug Exclusivity Regulations (8)Overview of Prior Clinical Studies of Rebif® (10)PROTOCOL XXXXXXXXXX (12)Objectives (12)Design (12)Material Source (13)Randomization (14)Inclusion Criteria (14)Exclusion Criteria (14)Treatment (15)Evaluations Performed During the Study (17)Efficacy Endpoints (21)Primary Endpoint (21)Secondary Endpoints (21)Tertiary Endpoints (21)Safety Endpoints (21)Safety Measurements Analyzed (21)Statistical Analysis Plan (22)Determination of Sample Size (22)Analysis Populations (22)Planned Interim Analysis (23)Significance Testing, Allocation of Alpha (23)Analysis of Baseline Parameters (23)Primary Endpoint – Proportion of Subjects Exacerbation-Free at 24 Weeks (24)Secondary Endpoints – MRI Analytic Methods (24)Safety Analyses (26)Study Administration (26)STUDY RESULTS (27)Formal Protocol Modifications (27)Changes in the Conduct of the Study or Planned Analyses (27)Protocol Deviations/Violations (28)Study Conduct at Specific Study Sites (30)Subject Enrollment and Disposition (31)Randomization (31)Time on Study (31)Time on Treatment: (32)Adverse Events Leading to Premature Discontinuation (33)Demographics and Baseline Characteristics (35)EFFICACY RESULTS (38)Primary Endpoint Results (38)CBER-Performed Analyses on the Primary Endpoint (42)Secondary Endpoints (48)MRI-Determined CU Activity (48)Exacerbation Rate per Subject (49)Mean Number of T2 Active Lesions per Subject per Scan (50)Tertiary Endpoints (51)Exploratory Analyses (53)Safety Analyses (55)Serious Adverse Events and Deaths (55)Important Rare Serious Adverse Events (58)Severe Adverse Events (59)Analysis by Body System and Event (60)Pregnancies (62)Development of Antibodies to Interferon-ß (62)Assessment and Conclusions (63)Financial Disclosure Statements (65)References (65)OverviewInterferon ß -1a (Rebif®) has been under development by Serono, Inc. for the treatment of multiple sclerosis (MS). Serono, Inc. submitted a Biologics License Application (BLA) on February 27, 1998 for the approval of Rebif® for the treatment of patients with relapsing-remitting MS (RRMS). The focus of the application was a 560-subject study that was a randomized, double-blind, placebo-controlled study of 22 µg vs. 44 µg Rebif® vs. placebo administered subcutaneously (SC) three times per week for 2 years. The application also contained additional open-label safety data from other studies. Based on the review of the BLA submission conducted by CBER, it was concluded that both doses of Rebif® were demonstrated to be safe and effective and to be approvable for treatment of RRMS. However, Serono was prevented from marketing Rebif® in the United States by the Orphan Drug Exclusivity previously granted to Biogen for the marketing of their interferon β-1a, Avonex® and to Berlex/Chiron for the marketing of their interferon β-1b, Betaseron® Betaseron®’s exclusivity expired in July 2000. Rebif® was, however, successfully approved and marketed in other countries, and thus has been commercially available in other portions of the world for several years. The subject of the current BLA amendment is a comparative study that Serono conducted to compare the efficacy of Rebif® to marketed doses of Avonex® in the treatment of relapsing-remitting MS. The study design was discussed with CBER and the design was agreed upon prior to initiation of the study. The study was a randomized, open-label study in which subjects with RRMS were treated with either Rebif® 44 µg SC three times per week or Avonex® 30 µg IM once weekly, with neurologic examinations performed by physicians blinded to the treatment assignment and with subjects’ MRIs read at a central reading facility by neuroradiologists blinded to treatment assignment. Although the duration of the study was to be 48 weeks, the pre-specified primary outcome measure was the proportion of subjects who remained relapse-free following 24 weeks of treatment. Supportive evidence (secondary endpoints) were comparisons of MRI abnormalities. The Applicant conducted and submitted this BLA amendment in the belief that demonstration of superior clinical benefit of Rebif® over Avonex® would allow them to break Biogen’s orphan drug exclusivity and thus, to market Rebif® in the U.S. for the treatment of relapsing-remitting MS.Scope of this reviewThe focus of this document is upon efficacy information obtained primarily from a single study, XXXXXXXXXX, a randomized, open-label comparative study of the use of Rebif® 44 µg administered SC 3x per week vs. Avonex® 30 µg administered IM once weekly. Efficacy and safety data from the BLA previously submitted by the Applicant and reviewed by CBER for the treatment of relapsing-remitting MS will be summarized. Safety data from several additional studies of Rebif® in MS, including safety data from the Applicant’s post-marketing safety database will also be summarized.Abbreviations and Definitions of Terms Used in This Review2-5 OAS 2’, 5’-oligoadenylate synthetaseADL Activities of Daily LivingAE Adverse EventALT Alanine TransaminaseANOVA Analysis of VarianceANCOVA Analysis of CovarianceAST Aspartate TransaminaseAvonex® Biogen’s recombinant human interferon β-1a BBB Blood-brain barrierBetaseron® Berlex’s human interferon β-1bCHO Chinese Hamster OvaryCRA Clinical Research AssociateCRF Case Report FormCU Combined Unique (T1 + T2)DER Drug Even t Report (form)EC Ethics CommitteeECG ElectrocardiogramEDSS (Kurtkze’s) Expanded Disability Status Scale Gd GadoliniumGd-DPTA Gadolinium-diethylenetriaminepentacetic acid HCG Human Chorionic GonadotrophinHLA Human Lymphocyte AntigenHTLV-1 Human T-cell lymphotrophic virus, type 1 IEC Independent Ethics CommitteeIFN InterferonIFN β-1a Recombinant human interferon β-1aIM Intramuscular (ly)IRB Institutional Review BoardIU International Unit(s)IUD Intrauterine deviceIV Intravenous (ly)KFS Kurtzke Functional Systemsmcg microgrammg milligram(s)mL milliliterMIU Million International Units (106 IU)MR Magnetic ResonanceMRI Magnetic Resonance ImagingMS Multiple SclerosisMSCRG Multiple Sclerosis Collaborative ResearchGroupNSAID Non-steroidal anti-inflammatory drugPRISMS Prevention of Relapses and disability byInterferon β-1a Subcutaneously in MultipleSclerosisprn as neededqod every alternate dayqw once weeklyRebif® Serono’s recombinant human interferon β-1aRRMS Relapsing-remitting multiple sclerosisSAE Serious Adverse EventSC Subcutaneous (ly)SGOT (AST) Serum glutamic oxaloacetic transaminaseSGPT (ALT) Serum glutamic pyruvic transaminaseSNRS Scripps Neurological Rating ScaleSPECTRIMS Secondary Progressive Efficacy ClinicalTrial of Recombinant Interferon-beta inMultiple SclerosisSPMS Secondary progressive multiple sclerosisT1 T1-weighted MRI scanning sequenceT2 T2-weighted MRI scanning sequencetiw three times per week t 1/2half-lifeµg microgram(s)ULN Upper Limit of NormalUSAN United States Adopted NamesUSP United States PharmacopoeiaWHO World Health OrganizationWHOART World Health Organization AdverseReaction TerminologyIntroductionMultiple SclerosisBackground and Diagnostic CriteriaMultiple Sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system of unknown etiology, although an autoimmune process has often been implicated. It is a common cause of neurological disability in young adults, primarily affecting people between 20 and 40 years of age, and affects women approximately twice as often as men. Although there are sometimes inconsistencies of terminology with regard to categorization of MS within the MS field, and although some persons with MS do not neatly fit into one of the following categories, it has often proved useful to discuss MS according to clinical course, in order to: 1) provide advice on prognosis, 2) incorporate this information into consideration of potential therapeutic choices, and 3) to improve homogeneity and thus chances for detecting clinically meaningful effects in designs of clinical trials of new therapies. Most experts in the field generally recognize three clinical forms of MS: relapsing-remitting, secondary progressive and primary progressive (Lublin and Reingold, 1996). Relapsing-remitting MS (RRMS) comprises the most common form at onset. It is the presenting form in up to an estimated 80-85% of subjects, and involves recurrent attacks of neurological symptoms and signs (relapses or exacerbations) involving multiple areas of the nervous system that occur at variable time intervals ranging from months to years between attacks. These exacerbations or relapses are followed by subsequent variable degrees of recovery (remissions). The majority of subjects with RRMS develop secondary progressive MS (SPMS) in which periods of stable recovery give way to neurological decline over time. About 50% of subjects with RRMS will develop the secondary progressive form of the disease within 10 years of onset; the proportion approaches 80% after 25 years (Runmarker and Anderson, 1993). Primary progressive MS is distinct from SPMS and is characterized by steady accumulation of neurological deficit from onset, without superimposed attacks or exacerbations; it affects a much smaller percentage of subjects, perhaps 10-20% of subjects with MS present with this form.Subjects with secondary progressive MS may continue to experience relapses; such subjects are then sometimes referred to as suffering relapsing-progressive disease; however, others (Weinshenker et al., 1989), use the term relapsing progressive MS to define subjects with a category they regard as exhibiting a mixture of primary progressive and secondary progressive disease, not simply a subset of secondary progressive MS. Such disparities in the use of terminology such as relapsing progressive account for some of the confusion in the literature regarding categorizations of MS beyond the three widely accepted categories of relapsing-remitting, secondary progressive and primary progressive disease. All experts agree, however, that there is a general tendency for the frequency of relapses to decline with time as the slowly progressive nature of the disease becomes more prominent. Weinshenker et al. in 1989 were amongst the first to provide comprehensive natural history data that supported the belief that progression of disability following conversion to SPMS is more rapid than prior to conversion.Several phases of pathological change occur in MS, including breakdown of the blood-brain barrier with edema, lymphocytic infiltration with cytokine release, demyelination and axonal loss. Functional impairment can occur with any of these pathological processes, but irreversible deficits are thought to result from demyelination and axonal injury. There is evidence from magnetic resonance spectroscopy (Arnold et al., 1994 and DeStefano et al., 1998) and pathological studies (Trapp et al., 1998 and Ferguson et al., 1997) that axonal dysfunction and loss can occur even at early clinical stages of the disease.Current Treatment of MSThere are currently four drugs approved for the treatment of MS in the United States. Betseron® (Interferon β-1b) and Avonex® (Interferon β-1a) have been demonstrated to have beneficial effects on relapsing-remitting MS. Betaseron® administered at a dose of 8 MIU SC every other day was demonstrated to decrease the frequency of clinical exacerbations in ambulatory patients with relapsing-remitting MS. Avonex® administered at a dose of 30 µg IM once weekly was demonstrated to decrease the frequency of clinical exacerbations and to slow the accumulation of physical disability as measured by Kurtzke’s Expanded Disability Status Scale (EDSS) score. Copaxone® (glatiramer acetate – formerly known as copolymer-1) administered at a dose of 20 µg SC once daily was demonstrated to decrease the frequency of relapses in patients with relapsing-remitting MS. All three drugs have consistently been shown to reduce the frequency of clinical exacerbations compared to placebo by approximately one-third. Their effects have never previously been compared directly in a clinical trial. Novantrone® (Mitoxantrone), a cancer chemotherapeutic agent, was approved in 2000 for reducing neurologic disability and/or the frequency of clinical relapses in patients with secondary (chronic) progressive, progressive relapsing, or worsening relapsing-remitting multiple sclerosis. However, its cumulative dose-limiting cardiotoxicity restricts its role in the treatment of MS.Other immunosuppressive agents, including cyclophosphamide, azathioprine and low-dose methotrexate have been demonstrated to have only modest effects in treating MS, and are not widely used in this country. Similarly, intravenous immunoglobulin infusions (IVIG) are felt by some to be effective in treating MS, but are not widely used in the U.S., and do not have an approved indication for the treatment of MS.The Orphan Drug Act and Orphan Drug Exclusivity RegulationsThe Orphan Drug Regulations in 21 CFR Part 316 were written to implement section 2 of the Orphan Drug Act of 1983, that consists of four sections added to the Federal Food, Drug, and Cosmetic Act. The Orphan Drug Act directs FDA to provide written recommendations on studies required for approval of a marketing application for an orphan drug. It also provides for the designation of drugs, including antibiotics and biological products, as orphan drugs when certain conditions are met, and it provides conditions under which a sponsor of an approved orphan drug enjoys exclusive approval for that drug for the orphan indication for 7 years following the date of the drug’s marketing approval.The orphan drug regulations state that “after approval of a sponsor’s marketing application…FDA will not approve another sponsor’s marketing application for the same drug before the expiration of 7 years from the date of such approval” (21CFR316.31(a)). The definition of “exclusive approval” clarifies that this exclusivity applies only to the same indication as the originator product’s approval (21CFR316.3(b)(12)).The definition of “same drug” (21CFR316.3(b)(13)) describes how to judge two products from different sponsors on a physical-chemical basis for different classes of molecules. For each description, however, a showing that the follow-on product is clinically superior to the originator product can supercede the structural determination of “same drug”.The definition of “clinically superior” (21CFR316.3(b)(3)) describes the criteria for judging the subsequent product clinically superior to the already approved product. A new product can be deemed clinically superior if it has shown greater effectiveness on a clinically meaningful endpoint. For this demonstration, “in most cases, direct comparative clinical trials would be necessary.” Alternatively, showing greater safety is adequate to deem a product clinically superior, with only “in some cases, direct comparative clinical trials” needed for this demonstration. Additionally, “in unusual cases, a demonstration that the drug otherwise makes a major contribution to patient care” can be adequate to deem the second product clinically superior to the already approved product.In 1993 Berlex Laboratories, in conjunction with Chiron, obtained marketing approval for their interferon β-1b product, Betaseron®, for treatment of relapsing-remitting MS. Berlex had previously obtained orphan drug designation for Betaseron® for treatment of MS, so that a 7-year period of marketing exclusivity for Betaseron® began with its approval. The clinical efficacy claim of the indication was for a decrease in the frequency of clinical exacerbations in ambulatory patients with relapsing-remitting MS.In 1996 Biogen, Inc. obtained marketing approval for their interferon β-1a product, Avonex® for treatment of relapsing forms of MS. Biogen had previously obtained orphan drug designation for Avonex® for treatment of MS. During the review of Biogen’s PLA for Avonex®, CBER determined that under the orphan drug regulations Betaseron® and Avonex® were deemed the same drug for purposes of determining marketing exclusivity when physical structure alone was considered. However, the two products were deemed different when the clinical data were considered. Avonex® treatment was found to have a significantly different and superior safety profile with regard to the incidence of injection-site skin necrosis, and was thus concluded to be a different drug from Betaseron® for orphan drug marketing exclusivity purposes. Consequently, Avonex® received marketing approval in 1996 and its own 7-year period of marketing exclusivity from its approval date. The clinical efficacy claim of Avonex®’s indication was to slow the accumulation of physical disability and decrease the frequency of clinical exacerbations in patients with relapsing forms of MS.Like Berlex and Biogen, Serono, Inc. was granted orphan drug designation for Rebif® for the treatment of MS. When they submitted a BLA in January of 1998 for the approval of their interferon β-1a product, Rebif®, for the treatment of relapsing-remitting and “transitional”MS, CBER determined that by structural comparison only, Rebif® was deemed to be the same product as either Betaseron® or Avonex® for orphan drug purposes, since two protein products that differ only in minor amino acid sequences or in glycosylation of the product are explicitly stated in the orphan drug regulations to be regarded as the same product. Consequently, clinical data remained the only mechanism by which Rebif® could possibly be determined to be not the “same drug” for orphan drug marketing exclusivity purposes. Following their review of the data submitted by Serono in the BLA filed in 1998, CBER concluded that Rebif® should not be given marketing approval while the existing marketing exclusivity accorded to Betaseron® (expired in 2000) and Avonex® (expires in 2003) remains in effect based on the following conclusions:FDA determined that on a solely structural basis, Rebif®, Betaseron® and Avonex® would be deemed the same drug, making clinically based information the only avenue for distinguishing th e drugs for use within the currently approved patient population. Consequently, there was no basis for determining that Rebif® is not the same drug as either Avonex® or Betaseron®, since• Serono had not submitted any information addressing a clinical comparison of Rebif® to Betaseron®;• Serono had not submitted adequate evidence to demonstrate that Rebif® has superior clinical efficacy or superior safety over Avonex®;• Serono had not submitted adequate evidence to demonstrate that Rebif® makes a major contribution to patient care over Avonex®;• Serono had not submitted adequate evidence to demonstrate that a medically plausible subset of subjects with MS, distinct from those for whom Avonex® is indicated, has been studied and shown to benefit from Rebif® where no benefit may be expected fromAvonex®.Although MS is no longer considered an orphan disease today because the prevalence is now known to be more than 250,000 in the U.S., the Orphan Drug Exclusivity regulations regarding marketing exclusivity still apply to the beta-interferons, since they were granted orphan drug status for the treatment of MS at a time when MS was estimated to affect fewer than 200,000 persons in the U.S.Overview of Prior Clinical Studies of Rebif®Serono has completed 6 controlled trials in MS along with a number of uncontrolled trials. Two studies were previously reviewed here in CBER in 1998-1999 as part of Serono’s initial BLA application for the approval of Rebif® for treatment of relapsing-remitting MS. Study GF 6789 was a 560-subject, multicenter, randomized, placebo-controlled trial that compared two doses of Rebif® (22 µg or 44 µg) vs. placebo administered SC three times per week for 2 years. The primary endpoint was the number of protocol-defined exacerbations per subject using the following definition of an exacerbation: “the appearance of a new symptom or worsening of an old symptom, attributable to MS, accompanied by appropriate new neurological abnormality, or focal neurological dysfunction lasting for at least 24 h ours in the absence of fever, and preceded by stability or improvement for at least 30 days.” Rebif®treatment significantly reduced the number at one and two years of treatment and the efficacy did not differ substantially between the two doses, nor was treatment with Rebif® associated with excessive numbers of dose-limiting toxicities. Rebif® treatment also showed a positive treatment effect on many of the secondary endpoints studied (not listed in order of importance by the Applicant prospectively), including effects on moderate/severe exacerbations, time to first exacerbation, proportion of subjects exacerbation-free, time to confirmed disability and percent progressors, decrease in MRI T2 lesion volume, decrease in combined T1 and T2 MRI “activity,” and reduction in hospitalizations and steroid treatment for MS. However, it was noted in the review that the incidence of “troubling” adverse events that included cytopenias and hepatic enzyme abnormalities were notably higher for the 44 µg dose than the 22 µg dose and both were higher than the rates observed in the placebo group. The percentages of these adverse events are shown in Table 1.Table 1: Cytopenias and Liver Enzyme Elevations in Study GF 6789WHOART preferred term PlaceboN=187 IFN 22µg TIWN=189IFN 44µg TIWN=184lymphopenia 11.2% 20.1% 28.8% leukopenia 3.7% 12.7% 22.3% granulocytopenia 3.7% 11.6% 15.2% thrombocytopenia 1.6% 1.6% 8.2%SGPT increased 4.3% 19.6% 27.2%SGOT increased 3.7% 10.1% 17.4%hepatic function abnormal 1.6% 3.7% 9.2%It was also noted in the review that one subject had developed a severe anaphylactoid reaction that was deemed probably due to the administration of Rebif®. It occurred approximately 1 month after treatment was begun and progressed over several days to “localized symptoms of urticaria, generalized pruritus and swollen red scars at the injection site.” Subsequent skin tests were said to have shown that the subject was allergic to a component in both the active drug and placebo. There was no increase in the incidence of depression or suicidal ideation or attempt in either treatment group compared to placebo. It was concluded that hematologic and hepatic toxicity was noticeably increased in a dose-dependent manner. Some of these abnormalities resulted in decisions to stop treatment. Although severe hematopoietic events occurred with greater frequency in active treated groups, there was no increase in infections. Hepatic enzyme abnormalities appeared to be isolated laboratory abnormalities. It w as also noted that there were noticeable increases of important injection site adverse events with Rebif® therapy, but rare discontinuation of treatment due to these events.A post-marketing report of “severe anaphylaxis with recombinant interferon β1a,” Rebif®, was submitted as a letter to the Editor in Neurology in 1999.XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX. Protocol XXXXXXXXXXTitle: An Open-Label, Randomized, Multicenter, Comparative, Parallel Group Study of Rebif® 44 µg Administered Three Times per Week by Subcutaneous Injection, Compared with Avonex® 30 µg Administered Once per Week by Intramuscular Injection in the Treatment of Relapsing-Remitting Multiple SclerosisPeriod of Study Conduct: November 1999 to February 2001Funding: Serono, Inc.ObjectivesThe primary objective as stated by the Applicant in the protocol was to demonstrate that the proportion of patients with relapsing-remitting MS who were exacerbation-free would be greater with Rebif® 44 µg administered three times per week (132 µg per week) than patients treated with Avonex® 30 µg once per week for 24 weeks.The principal secondary objective as stated in the protocol was that the MRI-determined combined unique (CU) lesion activity would be less after 24 weeks of treatment with Rebif® 44 µg three times per week than with Avonex® 30 µg once per week.DesignThis was a multicenter, open-label, randomized, comparative, parallel group study in which up to 624 interferon-naïve subjects with relapsing-remitting multiple sclerosis (RRMS) were to be equally randomized to receive either Rebif® 44 µg administered SC three times per week or Avonex® 30 µg administered IM once per week for 48 weeks. Although all enrolled subjects were to complete 48 weeks of the treatment to which they were randomized, the efficacy outcomes were to be determined after 24 weeks of treatment.T2-weighted and T1-weighted pre- and post gadolinium enhanced MRIs were obtained within 28 ± 4 days of beginning treatment and monthly thereafter following the start of treatment until Week 24. All pre- and post-treatment MRIs were read centrally at theXXXXXXXXXX, where the raters received only the subject’s identification number, initials, date of birth and whether or not the subject was to be scanned again.Each center was required to have two separate physicians responsible for the management of each subject: a treating physician and an evaluating physician. The treating physician was responsible for the supervision of study drug administration, for reporting and treating adverse events and monitoring safety assessments, and was also responsible for the treatment of exacerbations and for determining whether non-MS-related factors could account for neurological worsening. The evaluating physician was responsible for neurological assessments and evaluation of exacerbations, and was responsible for determining whether an apparent exacerbation met the protocol’s definition. The evaluating physician was to remain unaware of treatment assignments, adverse event profiles and any changes in safety assessments throughout the trial. Both the treating physicians and subjects were instructed not to discuss these issues with the evaluating physician.The primary study endpoint was the proportion of subjects who were exacerbation-free at 24 weeks. Subjects were instructed to inform the study center within 48 hours of the onset of an exacerbation, and at that time, the treating physician or designate would discuss the symptoms with the subject and determine whether a neurological examination was indicated. If so, the subject would be advised to come to the center for evaluation. The evaluating physician was to determine whether or not an exacerbation meeting the protocol’s definition had occurred, and would evaluate its severity based on changes in the EDSS and the Kurtzke Functional Systems (KFS) score.If the treating physician determined that corticosteroids were necessary for treatment of the exacerbation, a standard regimen of 1.0 g/day of IV methylprednisolone for three days was to be administered.Treatment discontinuation was mandatory in case of any of the following:1. Pregnancy2. Loss to follow-up3. Use of other investigational products, or4. Use of other approved disease-modifying therapy for MSTreatment could be discontinued for other reasons, but subjects were asked to continue the study assessments if they discontinued from the study prematurely.Material SourceRebif® was supplied as a sterile solution in pre-filled syringes for subcutaneous administration. Each syringe contained 0.5 mL of solution, which consisted of 44 µg (12 MIU) of interferon β-1a, 4 mg albumin (human, USP), 27.3 mg mannitol (USP), water for injection (USP) and XXXXXXXXXX for pH adjustment. The batch numbers used in this study were: XXXXXXXXXX.。
