Myopia has become a global public health concern due to its increasing prevalence and associated risks of sight-threatening complications. Although various evidence-based options are available to slow myopia progression, no treatment can completely halt it. High-risk patients, such as those with early onset, rapid progression, or poor response to standalone treatments, are often considered for combination treatments to enhance efficacy compared to single interventions. However, the exact mechanisms of action, patient selection criteria, and the magnitude of additional efficacy are still areas of ongoing investigation.
This article discusses significant considerations when researching studies evaluating combination treatments for myopia control. Knowing the limitations of these studies can help in making informed treatment decisions.
Definition of Combination Treatment
A clear definition of combination treatment is essential to classify each treatment category used in a study. An optical modality can be combined with a pharmaceutical agent. One example is the use of orthokeratology lenses with low-dose atropine eye drops. A combination approach can also involve the joined use of two optical modalities, such as using novel spectacles after removing multifocal contact lenses.
Choices of Control Group
Randomized Control: Randomized control designs offer the advantage of direct comparability between treatment and control groups but often have higher dropout rates in the control group due to difficulties in masking treatment allocation.
Virtual Control: Age- and ethnicity-matched virtual controls are increasingly used due to ethical concerns about assigning placebos to pediatric myopes with rapid refractive progression. This method leverages historical or real-world data, useful where untreated groups can't be used ethically. However, a major limitation of this control group is the lack of direct comparability and high risk of bias if virtual controls aren't appropriately matched to the treatment group. Additionally, most published normative databases are biased toward specific ethnicities, warranting further investigation into the validation of virtual controls for each specific trial.
Self-Control and Crossover Design: Self-controlled designs offer unique advantages by reducing inter-subject variability, since each participant acts as their own control, minimizing differences in genetics and lifestyle. Reduced variability means fewer participants may be needed to detect treatment effects, making the study more cost-effective. Additionally, ethical advantages simplify recruitment, as all participants receive active treatment. However, self-control designs also have disadvantages. For example, treatment effects persisting beyond the treatment phase can confound results, requiring a sufficient washout period to address this. Temporal effects, like seasonal variations in myopia progression rates, can complicate distinguishing treatment effects from time-related changes. The statistical analysis is more complex, needing careful adjustments for time and potential carryover effects. Also, these designs can increase the participant burden, as multiple treatment conditions may affect adherence and dropout rates.
Study duration
Myopia progression studies typically span 1-2 years at least to capture meaningful results. Longer studies are usually needed to understand the long-term effects of combination regimens compared to standalone treatments.
Washout and Rebound Effect
A washout period helps determine the persistence of treatment effects. The rebound effect, characterized by rapid myopia progression post-treatment, should be quantified to understand the true treatment impact. A washout period is especially relevant for treatments involving atropine, which has shown dose- and duration-dependent rebound effects.
Clinical value
In summary, in designing clinical studies for combination treatments for myopia control, balancing efficacy assessment with safety monitoring is crucial. Tailoring study designs to the unique characteristics of myopia progression and intervention effects is key to meaningful insights and guiding future treatment strategies. Further research should refine combination strategies and explore the mechanisms and long-term outcomes of such interventions. OM
