What's New in the Center for Clinical Research

CCR Offers Cardiovascular Ultrasound Imaging Service

Nancy Dalton performing a cardiac echo

The Center for Clinical Research (CCR) is pleased to announce a new Cardiovascular Ultrasound Imaging Service at the east campus clinic location. The CTRI has purchased a Philips Pure Wave HD15 ultrasound imaging system, with echocardiographic and vascular capabilities. A dedicated networked computer is attached to the ultrasound unit. All recordings will be stored on a secure server that is HIPAA compliant and maintained by the CTRI Biomedical Informatics team. Nancy Dalton, a registered cardiac sonographer, with certification in CIMT and BART scans, has been added to the CCR staff to perform the echos. Dr. Kirk Knowlton, Professor of Medicine and Chief of Cardiology, is providing medical expertise for this new research service.

Transthoracic echocardiography is available for clinical trials that have a need for cardiac imaging, cardiac output or cardiac phenotyping. Vascular echo procedures being offered include carotid artery intima media thickness (CIMT) and brachial artery reactivity testing (BART).

Vascular echo of neck vessels

“Echo studies can provide significant information to a researcher interested in cardiovascular status” said Dr. Mark Wallace, Director of the Center for Clinical Research. “They are a non-invasive and cost effective way to monitor cardiovascular changes that may occur from pharmacologic agents given during a research study or to determine the anatomy and function of the heart or blood vessels.”

Researchers interested in a consultation or investigators who want to utilize this service should complete a service request form.

A New Treatment for Patients with Severe Mitochondrial Disease

A 12-year-old participant in the EPI-743 study, with Donna Luna-Bautista, RN (Elmo costume) at the CTRI Clinic.

Mitochondria generate most of the energy in cells throughout the body, so defects in these intracellular structures can have far-ranging, sometimes devastating, consequences. Hundreds of mitochondrial diseases are currently known. They occur in both children and adults, and can affect multiple organs, including brain, heart, skeletal muscles, gastrointestinal tract, kidneys, peripheral nerves, eyes, and skin.

For these reasons, the clinical trial currently being conducted by Dr. Richard H. Haas, MD at the CTRI, and its encouraging preliminary results, are viewed with much interest by the clinicians, scientists, and families in the mitochondrial disease community. Along with Dr. Zuela Zolkipli-Cunningham and Dr. Gail Reiner, he is assessing the effects of EPI-743, an experimental agent developed by Edison Pharmaceuticals, as part of an international multicenter trial. The PI of the study, Dr. Greg Enns, is based at Stanford University.

According to Dr. Haas, a Professor in the Departments of Pediatrics and Neurosciences at the UC San Diego School of Medicine, the severity of the disease depends on the organs affected. “Most of us in the field view mitochondrial disease as similar to premature aging,” he says. “Whereas adults might most often be affected in the muscles and heart, children are mostly affected in the brain.” Dr. Zuela Zolkipli-Cunningham, an Instructor in the Department of Neurosciences and a pediatric neurologist, noted that “The earlier onset of mitochondrial disease in some children significantly impacts their neurodevelopment.” Developmental deficits include speech impairment, and often confine these children to wheelchairs. Most of the patients in the current study are likely to enter hospice within 6 months. “It’s tough to see them like that—kids are supposed to be bundles of energy, tiring out the adults first, not the other way around,” observed Vicky Lam, RN, Nurse Supervisor at the CTRI clinic. “And caregiver burden is usually pretty heavy with this population, especially since most of the families are from out of town and are willing to travel across the country to seek care for their children.”

There are two categories of mitochondrial disease: primary, due to a genetic defect; and secondary, as a component of other diseases like diabetes, Parkinson’s, and cancer. The children in the current study have diverse primary mitochondrial diseases, including MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes), Leigh’s Disease, and illnesses derived from deletions or depletions of mitochondrial DNA. However, the diseases typically share some common manifestations, such as disruptions in the electron transport chain (this is a series of molecular reactions inside mitochondria that give off energy). Besides interfering with energy production, impairment of electron transport can increase the number of free radicals (harmful molecules which also accumulate in the normal aging process).

So a goal of therapy for patients with mitochondrial disease is to remove or “scavenge” these free radicals, using antioxidants like coenzyme Q10 (CoQ10). In fact, the standard of care is a regimen of CoQ10, a high dose of the B vitamin riboflavin, and carnitine (plus supplemental folate for those patients with cerebral folate deficiency). However, CoQ10 is notoriously insoluble. So Edison Pharmaceuticals, the sponsor of the study, has formulated a version of CoQ10 that is more easily absorbed (it crosses the blood-brain barrier), and which seems to be a strong antioxidant. This soluble form of CoQ10 is combined with vitamin E to form the experimental agent EPI-743.

CoQ10 may help in another way. In addition to its antioxidant properties, CoQ10 happens to be one of the molecular players in the electron transport chain. So supplementation with CoQ10 may improve respiratory chain function in affected individuals, especially those patients who have abnormally low amounts of CoQ10 in their muscles.

This international multicenter trial involves a total of approximately 120 children and adults with mitochondrial disease, 8 of whom participate at the CTRI. Treatment consists of oral EPI-743 over 13 weeks. In addition, subjects take their usual regimen of high dose B vitamins including riboflavin and carnitine, but without their conventional CoQ10. The primary endpoint is quality of life, measured by the Newcastle Pediatric Mitochondrial Disease Survey.

“Since this is an open-label study, the results must be viewed with caution; but we are seeing benefits in development,” says Dr. Haas. This is consistent with three published reports on a similar regimen. Gail Reiner, Nurse Practitioner III and Research Coordinator for the study, added that “Ten-year-old Derek spoke for the first time in his life this week. ‘Hi,’ proud and four times. Amazing.” The treatment appears well-tolerated; some subjects experience gastrointestinal issues, but these have been readily resolved.

After 13 weeks, the patients will continue on therapy, with follow-up probably every 3 months. Beyond this open-label EPI-743 study, a new clinical trial has just started—the first randomized, double-blinded, controlled trial in Leigh’s Disease, including centers at Stanford University, Seattle Children’s Hospital, Akron Children’s Hospital, and Baylor College of Medicine. The endpoints include quality of life, survival rate, neuromuscular function, respiratory function, drug safety, and biomarkers. For more information on this new trial, please visit Safety and Efficacy Study of EPI-743 in Children With Genetically Confirmed Leigh Syndrome. Patients and their families can find information on mitochondrial diseases from the United Mitochondrial Disease Foundation.

Clinical Trial of Dark Chocolate in Heart Failure

Pam R. Taub, MD, a cardiologist and Assistant Clinical Professor in the UC San Diego Department of Medicine, thinks your heart and skeletal muscles could benefit when you eat dark chocolate—just not too much of it. After 5 years of research, including animal studies and one proof-of-concept clinical trial, she and Francisco Villarreal, MD, PhD, have recently embarked on a new clinical study at the CTRI Center for Clinical Research. The trial is designed to assess the effects of epicatechin, a flavanol in dark chocolate, on exercise capacity in subjects with advanced heart failure (HF) and type 2 diabetes mellitus (DM2). Both illnesses are characterized by mitochondrial disruptions, which her prior data suggest are improved with epicatechin administration.

In preclinical studies, rats pretreated with epicatechin and then subjected to ischemia/reperfusion exhibited myocardial infarcts that were much smaller than those in control animals. Beneficial effects of epicatechin were also seen in functional studies, where animals given epicatechin showed enhanced exercise capacity. At the subcellular level, these physiological effects were associated with marked improvements in mitochondrial structure.

In Dr. Taub’s first human clinical study, patients with class III HF, class II/III HF, or DM2 consumed an epicatechin-enriched cocoa plus a small amount of chocolate every day for 3 months. Skeletal muscle biopsies of the quadriceps femoris were carried out both before and after treatment. After treatment, Western blots showed statistically significant stimulation of indicators of mitochondrial biogenesis in all five subjects, and electron microscopy revealed a dramatic improvement in the density and orderly structure of cristae, the submitochondrial structures where oxidative phosphorylation occurs. “The fact that anything could improve in these profoundly ill, deconditioned patients is remarkable,” according to Dr. Taub.

The new clinical study in humans, a randomized, controlled, blinded trial at the CTRI, was begun in September 2012. It will enroll 10 healthy sedentary subjects and 10 subjects with DM2 or stage II HF. The effects of epicatechin and placebo on exercise capacity, morphology of skeletal muscle mitochondria, and quality of life measures will be compared between the two cohorts.

At the start of the study, all subjects will have multiple pretreatment assessments performed: VO2 max (maximal oxygen consumption during exercise), skeletal muscle biopsies, and MRS (a noninvasive MRI of muscle that measures indicators of energy metabolism); plus they will wear accelerometers (which count the number of steps walked) for 2 days, and fill out Quality of Life surveys. In the treatment phase, half of the subjects in each cohort will consume a small amount of epicatechin-enriched dark chocolate daily for 3 months, while the other half in each cohort will eat a placebo resembling dark chocolate, which does not contain epicatechin. Posttreatment, the same assessments that were done at baseline will be repeated, and the data for the two timepoints compared.

Dr. Taub performs the muscle biopsies herself. “Initially patients are apprehensive, but once they get one done, they realize it is not painful and just feel like they may temporarily have a sore muscle, and they agree to do it again.” The chocolate is supplied by the Hershey Center for Health and Nutrition, which sponsors public health initiatives. Clinical support is provided by the CTRI Clinical Research Services. “Vicky Lam and Dan Szpak, RNs at the clinic, are very accommodating, very much collaborative, willing to bend over backwards to implement a procedure that’s new for them,” Dr. Taub says. “We worked out lots of firsts—bicycle ergometry instead of the treadmill type, for example—procedures that other clinics might decline to set up de novo. And Cindy Knott, a Clinical Research Dietitian who helps with the exercise testing, is amazing.”

There are other advantages to working with the CTRI. Dr. Taub reports that the Office of Clinical Trials Administration, which collaborates with the CTRI, completed the contract with Hershey in a month. “The CTRI is fair in terms of cost. They also take care of many things for my patients—patient parking and so forth. I can focus on my research while they take care of the infrastructure.”

So if epicatechin improves mitochondrial biogenesis in skeletal muscles, could we call chocolate a performance-enhancing drug for athletes? “I think you can, actually. But everyone, including sedentary people, could benefit, not just elite athletes.” In fact, Dr. Taub and her colleagues would like to see a pill containing purified epicatechin be made available to consumers, so that they could avoid the less healthy components in commercial chocolate. “The dose-response curve for epicatechin seems to be bell-shaped, unfortunately. In other words, after a certain point, more is not better.” Another future goal is a clinical trial that would more directly examine the effects of epicatechin on the heart (using echocardiography, for example). But for right now, we can feel good about eating two small squares of dark chocolate per day.

Mark Wallace Receives Humanism Award

Dr. Mark Wallace and family at UCSD White Coat Ceremony, Fall 2012.

Mark Wallace, MD, Director of the CTRI Center for Clinical Research Services, was recognized with the Leonard Tow Humanism in Medicine Award at the recent White Coat Ceremony, UC San Diego School of Medicine. The Ceremony annually marks the time when first-year medical students receive their white coats, signaling the start of clinical studies. The nationally esteemed Humanism Award distinguishes clinicians who deliver compassionate care to their patients and families, and is accompanied by a $1,000.00 monetary prize.

Dr. Wallace, who is a Clinical Professor and Chair of the Pain Division within the Department of Anesthesiology, is a translational researcher focused on developing therapies, including cannabinoids, for treating certain clinical pain states. He also studies the correlation of human experimental pain models with those states, as well as the roles of receptors (opioid, adrenoreceptor, and NMDA) and ion channels on pain. Please join the CTRI in congratulating Dr. Wallace on his signal honor.