Diabetes: The Forgotten Disease

Diabetes is one of the largest therapeutic areas in terms of global pharmaceutical sales. The International Diabetes Foundation estimates in 2007 nearly U.S. $44 billion will be spent on diabetes pharmaceutical sales. Pharmaceutical companies are actively researching new therapies in the area of diabetes and are seeking strong partners to run efficient and effective studies. Currently, more than 1000 clinical trials are being conducted in the area of diabetes. There are many important aspects to consider in conducting a diabetic trial. However, relating to labs, the most important is imaging markers.

Photography: Dynamic Graphics Illustration: Paul A. Belci

Centralized imaging in trials

Utilizing imaging endpoints in diabetic clinical trials can be extremely effective. An example of this is a trial published in the November 13, 2006, edition of JAMA, "Effect of Pioglitazone Compared With Glimepiride on Carotid Intima-Media Thickness in Type 2 Diabetes." This study successfully utilized Carotid Intima-Media Thickness (CIMT) to demonstrate the effectiveness of pioglitazone with subjects who have type 2 diabetes.

There are multiple imaging endpoints that can be considered in diabetic clinical trials. Imaging modalities that would be utilized include ultrasound, CT, dual-energy, x-ray absorptiometry (DXA), MRI, retinal angiography, angiography, and quantitative coronary angiography (QCA).

Carotid artery intima-media thickness (IMT) is a marker of coronary atherosclerosis and independently predicts cardiovascular events. Image acquisition for IMT studies is more challenging than for sonographic exams performed for clinical routine. It is helpful when an imaging partner has arranged a specific training program for sonographers so they are able to conduct various types of acquisitions and get reproducible results.

In addition, specialized acquisition workstations that include a "mask" function allow the sonographer to find the same acquisition zone used during a previous exam. This technique has been widely used in long-term clinical trials and has allowed accurate retrieval of the artery segment for the measurement of IMT in carotid arteries.

Carotid IMT values vary tremendously during the cardiac cycle, sometimes by more than 50%, with a stable value for only a few milliseconds during the cycle. Stability occurs during the end diastole, which is why measurements must be done during this interval. Before reading, it is important to process video clips (exams) to extract the best end-diastolic image. Centralized readings assist in avoiding bias and inconsistency in the image preparation.

Computer-assisted techniques for the semi-automatic measurement of IMT avoid manual measurement. This type of software should be extensively validated against phantoms, cadaveric arteries, and echo-tracking. For improved consistency and efficacy, central reading should be divided into two steps: prereading performed by a clinical research technician and reading validation performed by a trained reader.

Precise and reproducible measurements

In trials on diabetic or obese patients, there is a need for reliable assessment of fat accumulation, fat loss, and lipodystrophy. These assessments are usually made by clinical examination and anthropometric evaluations, such as limb circumference. These methods, however, are imprecise and operator dependent. The use of noninvasive imaging techniques such as dual-energy x-ray absorptiometry (DXA) or high resolution CT (HRCT) allow a precise and reproducible quantitation of body fat and lipodystrophy, especially when coupled with computer-assisted measurement methods.

Each CT slice is evaluated to determine the cross-sectional area of body tissues. The most effective method is to utilize a semi-automated approach that employs image segmentation algorithms to define areas of adipose tissue (fat) and nonadipose tissue (muscles, bone, organs). The results should then be reviewed by a radiologist to ensure correct classification of tissues. The radiologist would adjust the computer algorithm as needed, and adipose tissue is further segmented into subcutaneous and visceral compartments (see Figure 1).

Figure 1. Example of abdominal scan: automatic calculation by the computer of subcutaneous fat (yellow) and peri-visceral fat (red).

CT is capable of distinguishing different tissue types based on their attenuation characteristics, which in turn are a function of tissue density and chemical composition. Because of the normally higher density of the liver compared to the spleen, a lower mean liver attenuation value relative to that of the spleen indicates fatty infiltration of the liver. Studies have shown a strong correlation between CT attenuation values in the liver and fatty infiltration measured by biopsy. The ratio of liver to spleen (L/S ratio) for CT attenuation values is another index, with <1 considered to represent fatty liver.

A single CT slice at T11/T12, which includes both the liver and spleen, is acquired by the sites. CT attenuation in liver (CTL) and in spleen (CTS) are obtained by identifying three regions of interest within each organ and then calculating the corresponding average density value. The regions of interest are placed by a trained radiologist in the parenchyma of the right lobe and left lobe of the liver and in a similar region of the spleen. In choosing regions of interest, blood vessels, artifacts, and areas of inhomogeneity are avoided.

It is important when choosing an imaging partner to ensure systems are fully compliant with FDA 21 Part 11 and readers are continually trained to ensure standardized high-quality and reproducible reads. There are several services an imaging provider should offer upon entering into an agreement:

• Technical consulting/protocol design and review

• Study documentation (site image acquisition manual, image analysis charter, etc.)

• Site recommendations and selection

• Site technical initiation and site study supplies

• Ongoing image collection and pro-active tracking

• Digital data translation and film digitization

• Real-time image quality control

• Reading plan design services based on FDA guidance

• Qualitative and/or quantitative review of study data with validated semi-automated software

• Regulatory submission

• Successful experience with FDA audits.

The future of diabetes

Focusing on protocols, quality controls, training, and methodologies are important considerations when including an imaging endpoint in a diabetic clinical trial. Clinical trial experience allows the delivery of better quality data, which can reduce trial costs and speed time to market. This is a disease that has not benefited from massive media attention or significant legislative action. Therefore, it is imperative that progress needs to take place in the global clinical trials arena.

Gary S. Velasquez, is president and chief executive officer of Synarc, and vice chair of the board of trustees for the Whittier Institute for Diabetes. Natalie A. Cummins* is director of corporate marketing and communications at Synarc, email: natalie.cummins@synarc.com

*To whom all correspondence should be addressed.