Ask the Mito Doc – March 2024; Q&A

Ask the Mito Doc – March 2024 Q&A



All answers today are based on personal experience of the participants. As always, please consult your personal physician prior to taking any action.


Topic: Clinical Trial Readiness: Preparing for 2024 and Beyond



Philip Yeske, PhD, UMDF Science & Alliance Officer

Zuela Zolkipli-Cunningham, MBChB, MRCP, Children’s Hospital of Philadelphia

Stephanie O’Leary, PT, Children’s Hospital of Philadelphia


Q: I went through all the testing for a UCSD clinical trial for mito myopathy and at the end was disqualified because I had a radical prostatectomy. Can you explain why?

A: Zuela Zolkipli-Cunningham, MD: Any clinical study needs to be very, very clear on the type of individuals that it aims to study. That’s the best way of saying it. How we start off as researchers, we need to deeply consider what would be the best approach. Studying a cohort of patients, which I explained earlier, that are very different to each other in terms of clinical symptoms and genetic etiologies, but that you’re having to focus in and hone in on a particular group that might look fairly similar because that’s going to increase our chances of finding positive results. That’s the best way putting it. Every grant submission I put in that’s always been the biggest focus. And therefore when we write our study protocols, a fundamental part of it is to come up with inclusion criteria and exclusion criteria. So inclusion criteria, what aspects of the symptoms or what aspects of your genetic etiologies that would make you qualify for participation in the trial. Some of that could be something as simple as you need to be fairly stable for 6 months before entering the study. And then exclusion criteria is really, really important to ensure your safety in the trial. So those will be factors like you don’t have an additional bleeding disorder or you don’t have an additional pulmonary problem that would make it impossible for you to complete all of these assessments. So inclusion and exclusion criteria are fundamental to any clinical trial in any clinical research study. When you reach out with your willingness, or when you express your willingness to participate, generally there’s always going to be a series of questions that the study coordinator will walk you through in order to see if you qualify to participate on not. Inclusion criteria could be something as simple as age. And sometimes, too, it’s worth saying I saw one of the questions that was being post here, if something happened to you that was unexpected or unrelated to your disorder, like if you had to have surgery for a broken hip, if there’s things that are unrelated and unexpected.


A: Philip Yeske, PhD: Yes, and I think we have to acknowledge it might be frustrating for the patient community sometimes to say, I have the genetic diagnosis, this is the disease that is being studied, but I’m still being excluded. And really, as you described, it’s because there’ these other factors that have to be considered to make sure their testing is as homogeneous a group of patients as possible to be able to get the clean read on the effect of the drug.



Q: Is a genetic diagnosis required for participants?

A: Zarazuela Zolkipli Cunningham, MD: I would say in most disorders, it’s necessary. If I might share some insight, when we’re planning our clinical studies we have to discuss the likelihood of success because otherwise there’s a lot of time being spent and a lot of sponsorship funding being spent and a lot of participants’ time, so the design of the study is really essential.

In mitochondrial disease, it’s a genetic diagnosis. At the end of the day, these are genetic disorders. They’re inherited genetic disorders. So having a genetic diagnosis for mitochondrial disease is now considered a standard request for most clinical research studies and all clinical trials in mitochondrial disease. Otherwise, you end up with potentially a cohort of people who are not all the same. You see, it’s not helpful to compare a person with, for example, a PolG mutation or MELAS disorder to the next person perhaps with diabetes with secondary mitochondrial dysfunction, but no evidence of genetic diagnosis. So again, streamlining the cohort to make it as similar as possible has always been the biggest focus because the biggest challenge of studying mitochondrial disease patients is that everybody is just a little bit different to each other. A homogeneous population doesn’t exist in our patient cohort, but trying to streamline is the biggest effort we can make in order to get positive results.


Q: Hello, if we have some solid supporting evidence/benefits of a medication that can help push a clinical trial, where do we start to initiate a clinical trial?

A: Nicole Wilson, UMDF: Please share with our Science & Alliance team – you can email Nicole directly at and she can look into the best path to share. We have a strong network of researchers, scientists and industry partners.


Q: Does the slow disease progression indicate that a drug treatment can be proven to be significant more easily because only a small clinical benefit is needed?

A: Zarazuela Zolkipli Cunningham, MD: Yes and no. Based on the data, the need is to show that the drug being tested has led to clear improvement, and not just to slow down the rate of decline.


Q: Can you tell us a little bit about informed consent and what that means?

A: Nicole Wilson, UMDF: I will start with saying informed consent is important for anything that you’re going to do. So whether that’s mitoSHARE or whether it’s joining a clinical research study. Basically what it is, is just making sure that we’re upholding the ethics, the ethicalness of these studies to a level that needs to happen. So that’s protecting your privacy, and making sure that you understand that whenever you are joining a platform like mitoSHARE and you’re inputting your data that whenever we are doing in helping research studies with surveys, that’s really important for clinical trials to get started is those survey results is that when that information is shared it’s all de-identified. So it’s just going in and looking over all of those terms and making sure that you’re aware that we’re making sure that your privacy is number one to us. You are just signing off that we’re doing what we’re supposed to do and you understand what it is that we need to do. Did that answer the question, Phil, do you have anything additional to add?

A: Philip Yeske, PhD: I think in general it’s unethical to conduct research if the person who’s being researched doesn’t understand the research that is being conducted. And so informed consent just ensures that you’ve been provided enough information so that you can understand what it is that you’re agreeing to participate in. And when we collect that, then it’s also an assurance that privacy and other aspects will be respected as well. Ethical oversight is the foundation of any good clinical research being done.


Q: Do you believe that if a trial drug failed because it had “wrong endpoints” (12MWT) that this same drug could show positive effects and approval with the tools you developed?

A: Zarazuela Zolkolpi Cunningham, MD: We don’t know the answer to this, but it certainly is the reason why we strive to develop new outcome measures that are meaningful to our patients. Having the right outcome measures is key to designing a trial.


Q: I participated in a study that did video assessments of certain ADLs… that a direction you also envision?

A: Zarazuela Zolkolpi Cunningham, MD: Yes, video assessments is a form of remote assessment. We have also developed an outcome measure that is remote assessment of function. The advantage of remote assessments is that the patient is being assessed in their home environment.


Q: In the natural history study, what happened to fatigability over the 60 months in MC patients?

A: Zarazuela Zolkolpi Cunningham, MD: This is a great question. We found that the muscle fatigue remained stable over time in most patients.



Q: What are the steps in a study? How do you bring it to the FDA? How does that work? How does it become an outcome measure that the FDA will look at?

A: Zarazuela Zolkipli Cunningham, MD: This is really important to share because this is really why we need participation. The first key is developing the outcome measures. So having the expertise and having the ability to conduct something like this on a fast timeline because of course our trials are descending upon us. What we did with the mito med cause Margaret, is we published it. So that’s the absolute first step. It needs to be peer reviewed, it needs to be assessed by other researchers out there who agree that you’ve done your study to the absolute highest level of rigor and reproducibility. And then once it’s out there and it’s published it’s depending on the study that you did, but this is what we did for the cause. It’s validated for your population. I also spoke to the FDA. There was a process developing this, which honestly it took 3 to 5 years to make this outcome measure. But it’s only one. We have several others in the pipeline. We have had to have discussions with the FDA, of course, to understand what their expectations are for what’s called an FDA approved outcome measure for what will be good enough for a clinical trial. We speak to other researchers who have done it and have validated measures to understand what it took to make sure an outcome measure is feasible and usable in a clinical trial and will be appraised as a very meaningful measure by the FDA.

So yes, all of that had to be done. You publish it, and then going forward, when you collect data like the actual history, that is the strongest level of evidence we can have for a clinical trial, in fact, to support the need and effectiveness of the drug, we submit it to the FDA either with the results of that trial or prior to. And that’s the process of having the outcome measures and the data, the actual history data, acknowledged and at a high standard and then useable to push this forward to a drug approval when we’re there with the right clinical trial and the right drugs. But it requires participation from the patient community. So thank you.



Q: What guidance or advice can you give to MC patients (who have muscle weakness and fatigue readily) to stay safe when they are exercising or trying to do PT? Doctors push exercise and PT, but it may do more harm than good at times.

A: Stephanie O’Leary, PT: So it’s definitely important to just be open and upfront with the PT that you’re meeting and they can assess what pieces of the assessment might be more difficult and talk you through that. If it is determined that it might be too difficult to complete the

majority of the assessment, then we can cross that bridge and see if it’s appropriate for that participant to continue, but we can certainly modify some of the results or if your strength for example is impacted because you happen to be in pain because you sprained your ankle, then we can make a note of that.



Q: Is there any wearable technology related to the safety during physical therapy? What might patients have at their disposal to be able to know when they’ve had too much physical therapy, or know when to cut back a little bit and to stay safe? How do you see that as we move into the future?

A: Stephanie O’Leary, PT: I probably would have to dive a little bit deeper into the research, but personally I feel like our smart watches are going to get even smarter and be able to detect more biomarkers and be more perceptive into different balance measures and things like that.

A: Zarazuela Zolkipli Cunningham, MD: Yeah, exactly. We understand that remote assessment, meaning when the patient is not in front of us and they’re reaching out for help, we’re often at a loss and having to rely on the information that they provide us. We’re working at Chop on an oxygen nano sensor that we’ve been working on since 2016. The idea there is that if we have this nano sensor implanted in our patients, then in fact it gives us a measurement of your oxygen consumption, which is a marker of your mitochondrial fitness and your muscle mitochondrial oxidative phosphorylation function. It would be incredible to have the similar approach to how glucose monitoring has transformed diabetes care. And so the answer to your question is yes, indeed, if somebody’s overworked themselves or caught an infection and suddenly not feeling too good, then remotely being able to understand what your own mitochondrial function is by use of a nano sensor, for example, will transform medical management for sure going forward.



Q: Does dexterity in hands include problems holding onto objects both small, light and heavy? I tend to drop things unexpectedly.

A: Stephanie O’Leary PT: Thanks for your question. What you are describing is likely related to weakness or muscle fatigue in your hands or wrists. Dexterity refers to how you are able to use your hand or fingers to manipulate objects. So for example buttoning your shirt, turning a coin in your hand, or being able to pick up something very small using your thumb and index finger. I hope that helps to clarify!



Q: So when and where is this next conference for patients to attend?

A: UMDF Mitochondrial Medicine 2024 Conference will take place in Cleveland, OH from June 27-29. The Clinical Research Pavilion will be open the entire time and we will have dedicated sessions about Clinical Trial Readiness and what we continue to learn will take place on Thursday, June 27. Please reach out to for any additional questions.



Q: Why should people participate in both clinical research and clinical trials? Can you give us a synopsis of the many reasons this is beneficial and what kind of message we want to leave with our patient community this evening.

A: Zarazuela Zolkipli Cunningham, MD: It’s your patient voice; patient participation is basically the patient voice. I started off by showing you the results of our survey. That was a patient voice telling us, these are the things that bother us, this is what we want to be fixed. I took that data and I designed an outcome measure based on that information. That was the first step in starting off my research program – by listening to the patient voice. I hope that informs you just how important your voice is in informing clinical researchers starting off clinical research studies, how to design it. What would be the hypothesis? What is the objective? All of that was based honestly on the results of that first survey that we published. Then going forward, everything just fell into place, making the right outcome measure, then following it over time. Now, making it better by bringing in digital assessments. The digital assessments may or may not work for our patient population. We don’t know when we started off the assessments at the UMDF last year. We didn’t know what to expect. Was it going to tell me not much more detail than the 6 min walk clinical assessment did? It turns out it did tell us more. So this is all successes that we would not have achieved without patient participation in all of these research studies.