Thank you we now have our power calculations for the Charcot 2 project? **#MSResearch #CrowdSpeak #Crowdacure #MSBlog**

"David Holden successfully completed all the lab work on the saliva samples and sent me the spreadsheet several weeks ago. I only managed to analyse them two days ago. We have achieved what we wanted to with the samples and now know how many people with MS shed virus in their saliva. This has allowed me to do two sets of power calculations for the proposed trial of our antiviral drug in pwMS."

"This is the summary, or headline, results. Before reading them I need to explain what some of the jargon or stats speak is. In summary sample size determination is the process of defining the number of observations, or replicates, to include in a clinical trial. The sample size is an important feature of any clinical study in which the goal is to make inferences about the population from which the study subjects are recruited. In practice, the sample size is critical to make sure we have sufficient statistical power to answer the question in hand; for example in our proposed study, do we have enough subjects to confident that our drug works in suppressing lytic EBV infection in the salivary glands of pwMS. Although the sample size calculation uses real data we have to make some basic assumptions, for example how effective we expect the drug to be when tested in pwMS. We also have to set other variables, i.e. the actual power of the study and the so called alpha. Traditionally in medical trials the power of studies is set at 80% or 90%, i.e. we have an 80% or 90% chance based on the number of subjects studied to get a positive result. In comparison, the alpha sets the level of significance we are prepared to accept; we typically set this at 5% using a one- or two-sided comparison. This means that if we get a significant result there is a 5% chance of the result being a false positive result. False positive results are not that uncommon in research, which is why we have to reproduce results in second, or follow-on, studies. Please also note the power calculations, i.e. the size of the study, determines its cost."

"In the Charcot Project 2 we are using viral shedding of EBV as a readout for antiviral drugs targeting EBV. If our lead drug Famciclovir suppresses virus in saliva then we will be confident of it also being suitable as a treatment for infectious mononucleosis. This hasn't escaped our attention, nor has the case report below. This is why IM is one of our major focuses going forward and forms part of Charcot 3."

"Some of you may ask why are you behind schedule in getting these results out? It is my fault I have too many balls in the air and not enough bandwidth or time to do everything I am involved in. One of my team has called me the bottleneck in the system. When we have our annual research strategy meeting in a few weeks time I am going to hopefully address this problem. May be I should be called Prof. Bottleneck rather than Prof G?"

"Once more, thank you for your support. The money raised has give us the necessary results that we can now use to develop a protocol for our next study. I sincerely hope we will now be able to leverage these results to get funding for our study."

Goldani. Treatment of severe infectious mononucleosis with famciclovir. J Infect. 2002 Feb;44(2):92-3.

We report a patient with severe acute infectious mononucleosis who was successfully treated with famciclovir. A 15-year-old male was admitted with a 6-week history of fever, malaise, generalized lymphadenopathy, and hepatosplenomegaly, the patient was acutely ill with a temperature of 39.0 degrees C. Oropharyngeal examination revealed enlarged tonsils partially obstructing the airways. EBV serology obtained during admission showed a positive Monospot test, virus capsid antigen IgM, 1:320, Epstein-Barr nuclear and early antigen, negative. After 72 hours of treatment with famciclovir(500 mg t.i.d.), the patient was afebrile with important regression of the lymphadenopathy, enlarged tonsils and hepatosplenomegaly. Because acute infectious mononucleosis may be associated with extensive and prolonged disease, the potential therapeutic role of famciclovir in the treatment of severe forms of the disease deserves further studies.

**CoI**: Team G are the recipients of a grant from Crowdacure that was used to perform this research.

"This is the summary, or headline, results. Before reading them I need to explain what some of the jargon or stats speak is. In summary sample size determination is the process of defining the number of observations, or replicates, to include in a clinical trial. The sample size is an important feature of any clinical study in which the goal is to make inferences about the population from which the study subjects are recruited. In practice, the sample size is critical to make sure we have sufficient statistical power to answer the question in hand; for example in our proposed study, do we have enough subjects to confident that our drug works in suppressing lytic EBV infection in the salivary glands of pwMS. Although the sample size calculation uses real data we have to make some basic assumptions, for example how effective we expect the drug to be when tested in pwMS. We also have to set other variables, i.e. the actual power of the study and the so called alpha. Traditionally in medical trials the power of studies is set at 80% or 90%, i.e. we have an 80% or 90% chance based on the number of subjects studied to get a positive result. In comparison, the alpha sets the level of significance we are prepared to accept; we typically set this at 5% using a one- or two-sided comparison. This means that if we get a significant result there is a 5% chance of the result being a false positive result. False positive results are not that uncommon in research, which is why we have to reproduce results in second, or follow-on, studies. Please also note the power calculations, i.e. the size of the study, determines its cost."

CrowdaCure EBV Viral Shedding Trial Power Calculation Output

Proposed Power Calculations for a 6-month study

In the INSPIRE samples, which collected monthly saliva for 6 months, 9 out of 20 subjects with MS (45%) shed EBV, i.e. had a detectable EBV virus in their saliva, on at least one occasion. Based on this data we are now able to do a power calculation of a trial to assess the ability of an antiviral drug to suppress EBV lytic reactivation in the salivary glands.
Power calculation 1: Based on the conservative assumption that the antiviral drug will only be 75% effective in suppressing EBV reactivation over 6 months with monthly salivary sampling we will need at least 29 trial subjects per arm. This calculation is based on having a power of 90% and an alpha of 5%.

Power calculation 2: Based on the conservative assumption that the antiviral drug will only be 80% effective in suppressing EBV reactivation over 6 months with monthly salivary sampling we will need at least 18 trial subjects per arm. This calculation is based on having a power of 80% and an alpha of 5%.

Proposed Power Calculations for a 3-month study

In the Sheffield cohort, which collected monthly samples for 3 months, 44 out of 119 subjects with MS (37%) shed EBV, i.e. had a detectable EBV virus in their saliva, on at least one occasion. Based on this data we are now able to do a power calculation of a trial to assess the ability of an antiviral drug to suppress EBV lytic reactivation in the salivary glands.
Power calculation 1: Based on the conservative assumption that the antiviral drug will only be 75% effective in suppressing EBV reactivation over 3 months, with monthly salivary sampling, we will need at least 38 trial subjects per arm. This calculation is based on having a power of 90% and an alpha of 5%.

Power calculation 2: Based on the conservative assumption that the antiviral drug will only be 80% effective in suppressing EBV reactivation over 3 months, with monthly salivary sampling, we will need at least 24 trial subjects per arm. This calculation is based on having a power of 80% and an alpha of 5%.

"Some of you may ask why are you behind schedule in getting these results out? It is my fault I have too many balls in the air and not enough bandwidth or time to do everything I am involved in. One of my team has called me the bottleneck in the system. When we have our annual research strategy meeting in a few weeks time I am going to hopefully address this problem. May be I should be called Prof. Bottleneck rather than Prof G?"

"Once more, thank you for your support. The money raised has give us the necessary results that we can now use to develop a protocol for our next study. I sincerely hope we will now be able to leverage these results to get funding for our study."

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Goldani. Treatment of severe infectious mononucleosis with famciclovir. J Infect. 2002 Feb;44(2):92-3.

We report a patient with severe acute infectious mononucleosis who was successfully treated with famciclovir. A 15-year-old male was admitted with a 6-week history of fever, malaise, generalized lymphadenopathy, and hepatosplenomegaly, the patient was acutely ill with a temperature of 39.0 degrees C. Oropharyngeal examination revealed enlarged tonsils partially obstructing the airways. EBV serology obtained during admission showed a positive Monospot test, virus capsid antigen IgM, 1:320, Epstein-Barr nuclear and early antigen, negative. After 72 hours of treatment with famciclovir(500 mg t.i.d.), the patient was afebrile with important regression of the lymphadenopathy, enlarged tonsils and hepatosplenomegaly. Because acute infectious mononucleosis may be associated with extensive and prolonged disease, the potential therapeutic role of famciclovir in the treatment of severe forms of the disease deserves further studies.

Labels: bottleneck, Charcot Project, Crowdacure, CrowdSpeak, power calculations