A Case Study in Neurotherapeutic Clinical Trial Design and Conduct

Early this summer, Cleveland Clinic researchers enrolled the first patient in a phase 1 trial of an investigational medication for treatment of cognitive impairment in people with multiple sclerosis (MS). Beyond being one of the first clinical studies of a therapy for this potential indication, for which no treatments currently exist, the study is notable for Cleveland Clinic’s role in its design and execution.

“The company developing the medication asked us if we could design the study for them,” says Robert Fox, MD, a neurologist with Cleveland Clinic’s Mellen Center for Multiple Sclerosis Treatment and Research and the study’s principal investigator. “We decided to take them up on the offer, and they ultimately asked us to conduct the trial as well. Cleveland Clinic has done a good bit of clinical trial design in the past in the neurological space. We have the comprehensive multidisciplinary expertise and the structural organization to make it happen efficiently, so it’s a service we look forward to continuing to offer going forward.”

An ideal research arrangement

Specifically, Cleveland Clinic entered into a consultant agreement with the medication’s developer. Drawing on diverse teams, they designed the trial protocol and the data safety and monitoring plan, developed the investigational new drug (IND) application to the FDA and developed a detailed budget for the trial.

“We tapped into the expertise of our MS clinical trial designers in the Mellen Center as well as the advanced imaging specialists in the Mellen Center’s radiology group,” explains Dr. Fox, who additionally serves as Vice Chair for Research in Cleveland Clinic’s Neurological Institute. “We also leveraged neuropsychologists from within our Neurological Institute as well as two teams from Cleveland Clinic’s Lerner Research Institute — biomedical engineers for advanced MRI analysis and biostatisticians from the Department of Quantitative Health Sciences.”

After the drug’s developer reviewed the full study plan, they offered Cleveland Clinic a contract to conduct the single-center phase 1 trial as well. “We accepted, as we have deep experience in all stages of clinical trials for neurological therapeutics and can leverage assets like our advanced, high-field 7T MRI scanner,” Dr. Fox explains. “This is an appealing type of arrangement, as small biopharmaceutical companies often aren’t staffed to design and implement clinical trials in-house. This gives Cleveland Clinic an opportunity to serve the scientific community by designing and running these trials as pure researchers, without the complications of owning the intellectual property.”

Focus of the study

The study involves the compound bryostatin-1, a naturally occurring macrolide derived from a marine invertebrate that has previously been studied in clinical trials as an anti-cancer agent and for treatment of Alzheimer’s disease (AD).

Bryostatin-1 is a potent modulator of protein kinase C (PKC), a property that AD-focused studies showed reduces levels of soluble β amyloid protein. In murine models of AD, this prevented or reversed loss of hippocampal synapses and prevented memory impairment, findings that helped spur interest in its use for cognitive impairment in MS.

In addition to being a PKC modulator, bryostatin-1 is a potential toll-like receptor 4 ligand, an enhancer of Th2 immune response, an antioxidant and an inducer of neurogenesis. Collectively, these properties suggest a number of potentially beneficial actions of the compound in the setting of MS, including neuroprotection, remyelination, synaptogenesis, improved cognition and an anti-inflammatory effect.

The study at a glance

With these mechanistic underpinnings and findings from studies of bryostatin-1 in AD, Dr. Fox and colleagues designed the current study in MS as a single-site, single-arm, single-dosage, phase 1 trial to assess the agent’s safety and tolerability in patients with MS. An additional exploratory objective is to evaluate any changes in clinical, imaging and cognitive measures as signals of potential efficacy.

The study will enroll 20 patients with a confirmed diagnosis of MS. Enrollees may be on any disease-modifying therapy for MS, assuming their disease activity is stable and a change in disease-modifying therapy is not expected.

Bryostatin-1 will be administered in a series of 45-minute intravenous infusions over a total duration of 26 weeks divided into two 11-week treatment courses with four weeks between each treatment course. Each 11-week treatment course involves an initial loading dose followed a week later by a series of five more doses given every other week. Patients will be followed for an additional 12 weeks starting two weeks after treatment completion, for 40 weeks in total.

The primary outcome measures are frequency of treatment-emergent adverse events and serious adverse events, as well as frequency of study medication discontinuation. The researchers will also assess for potential central nervous system inflammatory effects as detected by clinical monitoring and brain MRI.

Clinical evaluation will involve the following:

• Expanded Disability Status Scale assessment at four time points throughout the 40-week study period
• Lower and upper extremity function and cognition assessment at nine time points, using the Cleveland Clinic-developed Multiple Sclerosis Performance Test
• Quality of Life in Neurological Disorders (Neuro-QoL) assessment at four time points
• A short cognitive battery at nine time points, consisting of the Montreal Cognitive Assessment (MoCA), the Controlled Oral Word Association Test (COWAT) and a processing speed test
• An extensive cognitive battery at three time points, consisting of tests of verbal learning, visuospatial memory, judgment of line orientation, naming abilities, and executive function and sorting
• 7T MRI assessment at four time points, including various image sequences

“Our MRI studies will assess MS lesion volume, brain volume in different brain regions, default mode network node connectivity (for functional assessment), microstructural complexity of dendrites and axons, anatomical connectivity of the transcallosal motor pathway, axon density and dispersion and various measures of myelination , as well as looking for any new lesions,” Dr. Fox notes.

“The studies of bryostatin-1 in Alzheimer’s disease showed that bioactivity starts around eight to nine weeks after therapy initiation, so we’ve scheduled the first post-baseline MRI assessment shortly after that,” he adds.

“Beyond the primary safety and tolerability assessment, we'll be using this phase 1 trial to see which metrics seem to be moving the most with this treatment,” he says. “Our hope is that we can use those findings to design and power a phase 2 trial that would ideally be a comparative, placebo-controlled trial to better assess those metrics of interest identified from the phase 1 trial.”

A model to be emulated

Dr. Fox says Cleveland Clinic’s Neurological Institute and its collaborators across Cleveland Clinic are well positioned to do this type of trial design and conduct across many areas of neurological practice, from movement disorders to epilepsy and others.

“We have a well-established research program for therapeutic trials, along with an abundance of skilled staff in many different areas and a long track record of running multifaceted, interdisciplinary studies,” he concludes. “That track record extends from trial design to trial implementation and coordination, and from analysis of imaging and fluid biomarkers to sophisticated biostatistical data analysis. We welcome opportunities like this to help advance the next generation of treatments for neurological disorders.”