The CHAMP Study - Q&A With Professor Karla Zadnik

Our Q&A format is designed to explore a particular clinical topic, intervention, product or research paper with an expert. In this interview we chat with Professor Karla Zadnik, a legend in myopia research, on her involvement as Principal Investigator in the Childhood Atropine for Myopia Progression (CHAMP) study, exploring the outcomes of a novel formulation of low-concentration atropine.

Prof. Zadnik: The CHAMP Study is a three-arm, randomized, double-masked, placebo-controlled, Phase 3 study of NVK002 (atropine 0.01% and 0.02%), sponsored by Vyluma, Inc. Its first stage completed in mid-2022, was a three-year study of 576 children with myopia. It was conducted at 25 sites in the United States and Europe, and the randomization scheme was 1:1:2 (placebo:0.01%:0.02%). The study drug is packaged in sterile, single-dose ampules and is preservative-free.

Eligible children were aged 3-17 years, had at least -0.50 D of myopia but no more than -6.00 D, and had low astigmatism. Children with a history or current use of other myopia control treatments were excluded. Enrolled children's demographics included: 57% white children; 16% Asian children; 17% Black children; 29% of the children were Hispanic/Latino. Sixty-two percent of the enrolled children were at least nine years old, and 56% were female, and 68% of the enrolled children had myopia between -0.50 and -3.00 D. Eighty-three percent of the originally enrolled children completed the study. Primary outcome measures include spherical equivalent refractive error measured by cycloplegic autorefraction and axial length.

Prof. Zadnik: Great care was taken in the initial study design planning of the CHAMP Study. Its objective was to establish the safety and efficacy of at least one dose of NVK002 for the treatment of myopia progression in children. The rigor of the CHAMP Study includes the following. The CHAMP Study was three years in duration with losses to follow-up that were lower than the original sample size planning assumed. The CHAMP Study was placebo controlled across the full three years. The CHAMP Study used an atropine carefully formulated to be shelf-stable at room temperature, preservative-free, packaged in single-dose ampules, all unique features for a study of this size and scope. The CHAMP Study was the first such investigation based in the United States and Europe. The CHAMP Study was conducted during the COVID pandemic, which presented challenges that the sponsor and investigators worked hard to overcome.

Prof. Zadnik: First, NVK002 formulations (0.01% and 0.02%) were found to be safe in the CHAMP Study. No participants experienced a serious, ocular treatment-emergent adverse event. The side effects typical for low-dose atropine were few and far between (3.5% of children reported photophobia; 3.3% allergic conjunctivitis; 1% blurred vision).

Second, NVK002 0.01% was efficacious in slowing the progression of myopia as evidenced by both spherical equivalent refractive error and axial length measures at 36 months compared to placebo. Likewise, significantly more children randomized to NVK002 0.01% progressed in their myopia by less than -0.50 D at 36 months compared to placebo. NVK002 was efficacious in slowing axial elongation at 36 months compared to placebo but, paradoxically, did not show a significant difference for spherical equivalent refractive error. Possible explanations for this unexpected result could include the effects of COVID on clinical sites' shutdowns; a higher than expected placebo responder rate; less study drug compliance later in the study; and use of prohibited myopia control treatments among study participants.

Prof. Zadnik: We are actively performing additional analyses of the CHAMP Study data. Specifically, we are comparing the placebo arm refractive error and axial length data to myopic children in my Collaborative Longitudinal Evaluation of Ethnicity and Refractive Error (CLEERE) Study; we have found astonishing agreement between the two cohorts, even though the data were collected more than two decades apart.

We are investigating subgroups and find that efficacy is greater in lower myopes, regardless of age. This finding strikes me as vitally important to clinicians, especially those who might see a child with -0.75 D of myopia and think they should wait to see how fast the myopia progresses before starting treatment with low-dose atropine. CLEERE data have already shown that a given year's progression does not predict the next year's progression or lack thereof (Mutti et al., Optometry and Vision Science, 2022). Combining that with the CHAMP data about greater efficacy in lower myopes should compel clinicians to re-evaluate their "wait-and-see" inclinations.

A recent CHAMP Study analysis revealed that half the enrolled children experienced less than -1.00 D of myopic progression at 36 months compared to baseline. We will explore that further and disseminate that information going forward.

Stage 2 of the CHAMP Study is ongoing. At 36 months in, children were re-randomized to placebo, 0.01%, or 0.02%. (Children originally randomized to placebo were only eligible for re-randomized to active study drug.) These results will shed light on the issues of rebound following low-dose atropine treatment for myopia progression.

Prof. Zadnik: I have a key message about atropine and all new developments in myopia control. Read, read, read. Clinicians should become avid, active consumers of the ophthalmic literature in an unprecedented way. The field of myopia is rapidly evolving. Studies like CHAMP have a wealth of information for the clinician to consume and apply to the care of their pediatric patients. Today, to be uninformed is to practice at a substandard level. The field of eye care simply must be evidence based, and the competent clinician has to put together the myopia management picture with each new puzzle piece generated by research.

The CHAMP Study is unprecedented - carefully manufactured low-dose atropine administered in a large sample of children in the United States and Europe over three years with a full, three-year placebo treatment arm. It has demonstrated safety and efficacy in preventing myopic progression, especially in lower myopes.

Whilst research has shown low-concentration atropine to be effective in slowing myopia progression, most studies have utilized diluted or compounded forms of the medication, some with preservatives. The CHAMP study investigates the efficacy of a commercially prepared formulation in reducing the rate of myopic progression in a mixed ethnicity cohort.

There are several unique aspects to the CHAMP study that make it an invaluable addition to our understanding of topical atropine in myopia control. First, randomized controlled trials of atropine have typically been of one or two-years' duration^1,2 while this study is three years' duration. Second, the placebo group was followed, on placebo, for the full three years. Third, the carefully developed, preservative-free, shelf-stable formulation contrasts with topical atropine studies typically employing diluted or compounded formulations. More information is available in our article Compounded Atropine For Myopia Control: Safe And Effective Prescribing. Finally, the multi-site study across the United States and Europe expands the evidence-base of studies primarily undertaken in Asia.^1,2

More data on the CHAMP study will be reported at the 2023 Association for Research in Vision and Ophthalmology (ARVO) research meeting in late April. To echo Professor Zadnik's final message: stay tuned to keep learning!

• When To Prescribe Atropine For Myopia Control
• Case Study: Compounded Topical Atropine: Is Every Bottle The Same?
• The LAMP Study Data Over Three Years: 0.05% Atropine Leads And Minimally Rebounds