There is a great deal of variability when it comes to osteoarthritis (OA) clinical trial designs. From the type of drug being studied to the regulatory approach of the target market to the optimal route of administration, assessment selections must be carefully tailored to meet the unique needs of each individual trial.
1. Pick the right study type.
Standardized randomized, placebo-controlled studies with parallel design are the most common for chronic pain but are far from the only option. In some cases, a full factorial design is necessary to satisfy the combination product rule, which requires that sponsors show that the combination offers some benefit over individual medications.
Open-label titration and randomized withdrawal are options used mostly in opioid studies. For these medications, researchers go with lower doses to minimize side effects rather than looking to maximize efficacy with higher ones. While very rare, cross-over designs offer an acute method whereby patients are treat with one drug for a week followed by both the next and the other during the final week.
2. Use typical chronic pain trial designs with added disease-specific and patient global assessments.
This means incorporating a number of different assessments, including:
- Daily Diary Pain Assessment — a primary pain assessment used in many different conditions
- Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Knee injury and Osteoarthritis Outcome Score (KOOS) — OA-specific improvement measurements
- Patient Global Impression of Change — overall improvement over time
- SF-36 — evaluates patient health
- Quality of life surveys
3. Make sure your study is long enough.
While shorter studies were acceptable in the past, the minimum duration of treatment for today’s OA studies is 12 weeks, the FDA recommendation for treatments of chronic conditions.
4. Pain should be the primary endpoint.
Improvement must be seen here to move forward with development and eventual approval. However, both WOMAC and KOOS are specific to OA of the knee and are often used as secondary endpoints.
5. Assess pain with average daily pain scores.
Primary subjective pain endpoints are usually measured with an 11-point numerical rating scale (NRS) and evaluated based on the difference of the weekly average of daily pain scores between baseline and the last week of treatment. Efficacy is never measured with a single data point — OA is cyclical with good days and bad days, resulting in high variability day to day.
6. Consider area under the curve-type measures.
An important alternative preferred in the European Union, area under the curve-type measures may be applied to pain intensity scores collected over the course of the treatment period. This method compares the entire treatment period instead of landmarks.
7. Make patient data reporting simple and consistent.
The ePRO diary is the most common method of collecting daily pain scores, as well as other easily answered measures, such as sleep and rescue medication use. To decrease human case report form entry error and CRA monitoring time, ePRO tablets and interactive response technology (IRT) websites have been used for in-office assessments, particularly longer ones. This allows for real-time data collection and more exact pain scores for the desired time. Under these systems, patients are given a window to respond. If data is not entered during that time, then the data is missed.
8. Tailor study design to specific product capabilities and challenges.
For example, single-entity opioids are usually studied using an open-label titration, randomized withdrawal design. In contrast, topical products often incorporate a placebo run-in phase to desensitize patients to any cooling effects of the vehicle.
9. Define the rescue drug.
Most OA pain studies use acetaminophen for rescue at a maximum of three grams per day regardless of the class of the drug being studied. Rescue use may be considered as a secondary endpoint.
10. Pay close attention to patient safety and qualification.
Osteoarthritis patients can belong to a number of vulnerable populations. The condition is also comorbid with a number of serious disorders that must be accounted for during patient selection and throughout the course of the trial. Depression and suicidality are of particular concern when working with pain patients and especially when a treatment plan involves opioids.
As such, a number of mental health assessments are often incorporated into OA study design to both exclude at-risk patients at recruitment and to monitor potential side effects. These include:
- Hospital Anxiety and Depression Scale (HADS)
- Beck Depression Inventory (BDI)
- Mini International Neuropsychiatric Interview (MINI)
- Columbia-Suicide Severity Rating Scale (C-SSRS)
Just as important a consideration, physical health measures necessary for patient selection — especially to rule out life-threatening cardiac complications — typically include:
- Basic blood work
- Wells’ Criteria for Pulmonary Embolism
- Cognitive assessments to measure ability to consent to and comply with study responsibilities