Matching-adjusted indirect comparison of phase 3 clinical trial outcomes: OC-01 (varenicline solution) nasal spray and cyclosporine A 0.05% ophthalmic emulsion for the treatment of dry eye disease

Study Design

BID, twice daily; STS, Schirmer’s test score.
1. Wirta D. et al. Ophthalmology. 2022;129:379–387; 2. Visco DM. et al. J Manag Care Spec Pharm. 2022;28:892–902; 3. Medical Review of NDA 21-023 2. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21-023_Restasis_Medr.PDF.

Endpoints Common to Both Trials

  • Mean change from baseline in STS with anesthesia
    • ONSET-2 at 2 and 4 weeks vs CsA trials at 3 and 6 months
  • Proportion of subjects with ≥10 mm improvement in STS with anesthesia
    • ONSET-2 at 4 weeks vs CsA trials at 6 months
CsA, cyclosporine A; STS, Schirmer’s test score.
Visco DM. et al. J Manag Care Spec Pharm. 2022;28:892–902.

Strengths and Limitations of MAIC Design

MAIC, matching-adjusted indirect comparison.
1. White D. et al. J Manag Care Spec Pharm. 2023;29:69–79; 2. Signorovitch JE. et al. Value Health. 2012;15:940–947; 3. Choy E. et al. Arthritis Res Ther. 2019;21:32; 4. Visco DM. et al. J Manag Care Spec Pharm. 2022;28:892–902.

ONSET-2 vs CsA Trials Results

Baseline Characteristics With Weighting

  • Matching-adjusted indirect comparison (MAIC) is a validated and widely accepted statistical methodology for cross-study comparisons after adjusting for baseline characteristic imbalances. It is a comparative analytical approach used across therapeutic areas absent of head-to-head trial outcomes.1,2
  • Baseline characteristic imbalances are adjusted by weighting individual patient data on all available clinically relevant baseline characteristics to create an adjusted dataset that matches the aggregate data of the comparator on the characteristics.1
  • This minimizes imbalances among patient characteristics between study samples that could bias unadjusted cross-study comparisons of treatment outcomes.1
1. Visco DM. et al. J Manag Care Spec Pharm. 2022;28:892–902; 2. White D. et al. J Manag Care Spec Pharm. 2023;29:69–79.

ONSET-2 vs CsA Trials Results

Baseline Characteristics With Weighting

*In the CsA trials, the continuous variable STS was reduced to a categorical 5-point variable as follows: 1 (<3 mm), 2 (3–6 mm), 3 (7–10 mm), 4 (11–14 mm), and 5 (>14 mm). All ONSET-2 data were recoded to match this scale.
CsA, cyclosporine A; MAIC, matching-adjusted indirect comparison; STS, Schirmer’s test score.
Visco DM. et al. J Manag Care Spec Pharm. 2022;28:892–902.

ONSET-2 vs CsA Trials Results

Efficacy Outcome Measures – Common Endpoint

Mean change in STS (with anesthesia) category* from baseline

Weighted results of LS mean change from baseline in STS with anesthesia for ONSET-2 and CsA trials. p-values are for treatment vs control at each time point; *In the CsA trials, the continuous variable STS was reduced to a categorical 5-point variable as follows: 1 (<3 mm), 2 (3–6 mm), 3 (7–10 mm), 4 (11–14 mm), and 5 (>14 mm). All ONSET-2 data were recoded to match this scale.
CI, confidence interval; CsA, cyclosporin A; LS, least squares; STS, Schirmer’s test score; VNS, varenicline solution nasal spray.
Visco DM. et al. J Manag Care Spec Pharm. 2022;28:892–902.

ONSET-2 vs CsA MAIC Outcomes

Efficacy Outcome Measures – Common Endpoint

Mean change in STS (with anesthesia) category* from baseline

Results of ANOVA models assessing the LS mean change from baseline in STS with anesthesia for ONSET-2 and CsA trials. p-values are for treatment vs control at each time point;*In the CsA trials, the continuous variable STS was reduced to a categorical 5-point variable as follows: 1 (<3 mm), 2 (3–6 mm), 3 (7–10 mm), 4 (11–14 mm), and 5 (>14 mm). CsA data was pooled from -002 and -003 CsA phase 3 studies. All ONSET-2 data were recoded to match this scale.
ANOVA, analysis of variance; CI, confidence interval; CsA, cyclosporin A; LS, least squares; STS, Schirmer’s test score; VNS, varenicline solution nasal spray.
Visco DM. et al. J Manag Care Spec Pharm. 2022;28:892–902.

ONSET-2 vs CsA Trials Outcomes

Efficacy Outcome Measures – Common Endpoint

Proportion of subjects with ≥10 mm improvement in STS with anesthesia from baseline

Weighted results of responder analyses of the proportions of subjects with a ≥10 mm improvement in STS with anesthesia for ONSET-2 and CsA trials. p-values are for treatment vs control at each time point.
CI, confidence interval; CsA, cyclosporin A; LS, least squares; STS, Schirmer’s test score; VNS, varenicline solution nasal spray.
Visco DM. et al. J Manag Care Spec Pharm. 2022;28:892–902.

ONSET-2 vs CsA MAIC Outcomes

Efficacy Outcome Measures – Common Endpoint

Proportion of subjects with ≥10 mm improvement in STS with anesthesia from baseline

Results of responder analyses of the proportions of subjects with a ≥10 mm improvement in STS with anesthesia for ONSET-2 and CsA trials. p-values are for treatment vs control at each time point.
ANOVA, analysis of variance; CI, confidence interval; CsA, cyclosporin A; LS, least squares; STS, Schirmer’s test score; VNS, varenicline solution nasal spray.
Visco DM. et al. J Manag Care Spec Pharm. 2022;28:892–902.

ONSET-2 vs CsA Trials Outcomes

Summary of MAIC Analysis

  • VNS 0.03mg vs. CsA 0.05% Phase 3:
    • Statistically significant difference in mean change from baseline STS for all comparisons
      • VNS at 2 and 4 weeks compared to CsA at 3 and 6 months
    • Statistically significant difference in proportion achieving ≥10 mm increase from baseline in STS (combined trials for CsA)
    • VNS at 4 weeks compared to CsA at 6 months in study -002 and study -003
    • CsA, cyclosporin A; MAIC, matching-adjusted indirect comparison; STS, Schirmer’s test score; VNS, varenicline solution nasal spray.
    Visco DM. et al. J Manag Care Spec Pharm. 2022;28:892–902.