Comparative Study of Dorzotimol Eye Drops, 20 mg/mL + 5 mg/mL Versus Cosopt® Eye Drops, 20 mg/mL + 5 mg/mL
Condition: Primary Open Angle Glaucoma of Both Eyes
MeSH terms: Glaucoma; Glaucoma, Open-Angle
Study type: Interventional
Phase: Phase 3

Summary: 
      The goal of this study is to compare efficacy and safety of Dorzotimol eye drops, 20 mg/mL +
      5 mg/mL manufactured by JADRAN-GALENSKI LABORATORIJ d.d. (Croatia) aimed at lowering elevated
      IOP in patients with ocular hypertension and primary open-angle glaucoma (POAG) versus
      Cosopt® eye drops, 20 mg/mL + 5 mg/mL manufactured by Laboratoires Merck Sharp &
      Dohme-Chibret, France. The main questions it aims to answer are:

        -  if the efficacy of the investigational drug and the reference drug in patients with
           ocular hypertension and primary open-angle glaucoma is equal;

        -  if the safety of the investigational drug and the reference drug in patients with ocular
           hypertension and primary open-angle glaucoma is equal.

      A total of 110 participants were screened and randomized 1:1 to the investigational drug
      (Dorzotimol) group or the reference drug (Cosopt) group. 55 patients were recruited in each
      group.

      Researchers compared the investigational drug (Dorzotimol) group with the reference drug
      (Cosopt) group to see if the efficacy and safety of the investigational drug and the
      reference drug in patients with ocular hypertension and primary open-angle glaucoma are
      equal.
    

Detailed description: 
      Study Title:

      An open-label, randomized, controlled, comparative efficacy and safety study of Dorzotimol
      eye drops, 20 mg/mL + 5 mg/mL, manufacturer: JADRAN - GALENSKI LABORATORIJ d.d., Croatia, vs.
      Cosopt® eye drops, 20 mg/mL + 5 mg/mL, manufacturer: Laboratoires Merck Sharp &
      Dohme-Chibret, France, in patients with primary open-angle glaucoma.

      Protocol No. DORZOTIMOL-10/2015, version No. 1.2 of 16.05.2017. RCT No. 632 of 09.09.2016.

      Investigators:

        1. Abdulaeva Elmira Abdulaevna (Test facility No.4)

        2. Eryomina Alyona Victorovna (Test facility No.6)

        3. Lisitsyn Alexey Borisovich (Test facility No.7)

        4. Doga Alexander Victorovich (Test facility No.9)

      Test facilities:

      No.4. State autonomous healthcare institution 'Republican Clinical Ophthalmological Hospital
      of the Ministry of Health of the Republic of Tatarstan', 420012, Republic of Tatarstan,
      Kazan, Butlerova St., 14.

      No.6. Federal state autonomous institution 'Acad. S.N. Fyodorov Eye Microsurgery Interbranch
      Science and Technology Complex', Ministry of Health of the Russian Federation, 127486,
      Moscow, Beskudnikovsky Blvd., 59A (branch: 630071, Novosibirsk, Kolkhidskaya St., 10).

      No.7. State healthcare institution of Yaroslavl region 'Clinical Hospital No. 8', 150030,
      Yaroslavl, Suzdalskoe Highway, 39.

      No.9. Federal state autonomous institution 'Acad. S.N. Fyodorov Eye Microsurgery Interbranch
      Science and Technology Complex', Ministry of Health of the Russian Federation, 127486,
      Moscow, Beskudnikovsky Blvd., 59A

      Study period:

      First patient enrollment date: 10 April 2017 Study completion date: 17 September 2018

      Phase:

      III (a safety and efficacy study)

      Study objective:

      The study objective was to evaluate the efficacy and safety of Dorzotimol eye drops, 20 mg/mL
      + 5 mg/mL, manufacturer: JADRAN - GALENSKI LABORATORIJ d.d., Croatia, designed to reduce
      elevated intraocular pressure in patients with primary open-angle glaucoma (POAG), vs.
      Cosopt® eye drops, 20 mg/mL + 5 mg/mL, manufacturer: Laboratoires Merck Sharp &
      Dohme-Chibret, France.

      Study tasks:

        -  Demonstrate sufficient similarity of the efficacy profiles of the test and reference
           product in patients with primary open-angle glaucoma.

        -  Demonstrate sufficient similarity of the safety profiles of the test and reference
           product in patients with primary open-angle glaucoma.

      Study design:

      A multicenter, prospective, open-label, randomized, comparative, controlled, parallel-arm
      study evaluating the efficacy and safety in patients with a specific disease.

      Study subjects: 110 patients (55 patients in each group) with elevated intraocular pressure
      induced by primary open-angle glaucoma (POAG), males and females in the age bracket of 18 to
      75 years conforming to the inclusion/exclusion criteria.

      Patients randomized: 110 Dropouts: 0 Per protocol population: 110 Safety population: 110 Drug
      therapy type

      Test product:

      Trade name: Dorzotimol INN or generic name: dorzolamide+timolol Pharmaceutical form: eye
      drops

      Composition per 1 mL:

      Active ingredients: dorzolamide hydrochloride 22.25 mg (equivalent to dorzolamide 20 mg),
      timolol maleate 6.83 mg (equivalent to timolol 5 mg).

      Excipients: benzalkonium chloride (as 50% solution), mannitol, sodium citrate, sodium
      hydroxide, hydroxyethyl cellulose, purified water.

      Manufacturer: JADRAN - GALENSKI LABORATORIJ d.d., Croatia Posology and method of
      administration: Instillation into the conjunctival sac of 1 drop twice daily for 12 weeks.

      Reference product description and labeling:

      Trade name: Cosopt® INN or generic name: dorzolamide+timolol Pharmaceutical form: eye drops

      Composition:

      Active ingredients: dorzolamide 20 mg (dorzolamide hydrochloride 22.26 mg) and timolol 5 mg
      (timolol maleate 6.83 mg).

      Excipients: benzalkonium chloride (as 50% benzalkonium chloride solution) 0.075 mg (0.15 mg),
      sodium citrate 2.94 mg, mannitol 16.00 mg, hyetellose (hydroxyethyl cellulose) 4.75 mg, 1M
      sodium hydroxide solution q.s. to рН 5.6, water for injection q.s. to 1 mL.

      Manufacturer: Laboratoires Merck Sharp & Dohme-Chibret, France Study duration: Screening: 7
      days. Washout period: 7 days. The comparison product treatment lasted for 12 weeks (84±2
      days), which was consistent with the reference product PIL. Follow-up period for safety
      evaluation: 7 days. The overall study duration per patient did not exceed 100 days.

      The efficacy was established based on analysis of the parameters as follows:

      Primary endpoint

        -  Mean IOP change from baseline. Secondary endpoints

        -  IOP reduction rate to the target level of ≤ 18 mm Hg.

        -  IOP reduction rate greater than 20%.

        -  IOP reduction rate greater than 30%. Safety evaluation

        -  Incidence of other adverse events to a greater or lesser extent linked to the test or
           reference product, including those evaluated from laboratory test findings.

        -  Treatment safety will be assessed from recording adverse events via analysis of
           complaints and symptoms, evaluation, and interpretation of the findings of instrumental
           monitoring (biomicroscopy, ophthalmoscopy, IOP measures, perimetry) and laboratory
           tests.

        -  Given that the test product may cause miosis resulting in transient visual acuity
           reduced, the contribution of the visual acuity parameter 'Vis' is not taken into account
           when assessing the treatment success.

      Statistical analysis Statistical analysis was performed using Statsoft Statistica
      Professional 13 and Microsoft Excel 2016 software.

      The Shapiro-Wilk test was used to evaluate the normality of distribution of quantitative
      attributes. Parametric tests were used for testing statistical hypotheses for parameters with
      the normal distribution, whereas nonparametric tests were used for parameters with the
      variance of the distribution. Student's t-test and Mann-Whitney U test were used for
      comparing the study groups in terms of quantitative attributes. The comparison of intragroup
      parameters before and after treatment was performed using the dependent samples t-test or the
      Wilcoxon test. The intragroup comparisons were also performed using nonparametric repeated
      measures ANOVA (the Friedman test). Qualitative attributes were analyzed using Pearson's χ2
      test or Fisher's exact test (if the attribute incidence rate in at least one subgroup was ≤
      5).

      Statistically significant are differences with p-values < 0.05. Efficacy analysis of the
      comparison products provides for a conclusion on

      • Noninferiority of the test product Dorzotimol, eye drops (JADRAN - GALENSKI LABORATORIJ
      d.d., Croatia) vs. reference product Cosopt®, eye drops (Laboratoires Merck Sharp &
      Dohme-Chibret, France) by the primary endpoint:

        -  No statistically significant intergroup differences have been observed regarding a mean
           intraocular pressure change from baseline either in the treatment or control group (p =
           0.0939; Mann-Whitney U test).

        -  The efficacy differences between the test and reference product by the primary criterion
           do not exceed the noninferiority margin of 1.5 mm Hg.

      Intergroup efficacy comparisons of the comparison products by the secondary endpoints have
      also been performed, with statistical significance of intergroup differences evaluated:

        -  No statistically significant intergroup differences have been observed regarding the IOP
           reduction rate to the target level of ≤ 18 mm Hg either in the treatment or control
           group (p = 0.3061; Pearson's χ2 test), which is indicative of Dorzotimol noninferiority
           by this parameter vs. reference product.

        -  No statistically significant intergroup differences have been observed regarding the IOP
           reduction rate greater than 20% at visit 6 from baseline either in the treatment or
           control group (p = 0.6336; Pearson's χ2 test), which is indicative of Dorzotimol
           noninferiority by this parameter vs. reference product.

        -  No statistically significant intergroup differences have been observed regarding the IOP
           reduction rate greater than 30% at visit 6 from baseline either in the treatment or
           control group (p = 0.4492, Pearson's χ2 test), which is indicative of Dorzotimol
           noninferiority by this parameter vs. reference product.

      The product safety was assessed from the vital parameters evaluation results, laboratory test
      and instrumental monitoring data as well as the adverse event occurrence and severity.

      The safety evaluation provided for the conclusions as follows:

        -  Analysis of these AEs is indicative of comparable safety of the test product:

             -  AE occurrence in the treatment group does not differ reliably from AE occurrence in
                the control group (p = 0.3242; Pearson's χ2 test).

             -  AE link to the test product was most characterized as 'probable'; there were no
                statistically significant intergroup differences by this parameter either (p =
                0.2774).

             -  AE severity was most characterized as mild; there were no statistically significant
                intergroup differences by this parameter either (p = 0.4309).

        -  There were no statistically significant intergroup differences either when assessing
           physical examination parameters or in terms of individual dynamics level.

        -  Analysis of the patients' laboratory test findings has identified statistically reliable
           differences by certain parameters (hemoglobin, glucose levels); however, these
           differences are also linked to patients' personality traits.

      Thus, based on all criteria specified in the Clinical Trial Protocol, the test product
      Dorzotimol and reference product Cosopt® demonstrate close efficacy and safety parameters.
      There are no statistically significant intergroup differences by any efficacy criteria
      tested. The efficacy differences between the test and reference product by the primary
      criterion do not exceed the noninferiority margin of 1.5 mm Hg. The above-stated provides for
      a conclusion on the test product Dorzotimol noninferiority vs. reference product Cosopt®.
    

Intervention name(s): Dorzotimol eye drops, 20 mg/mL + 5 mg/mL; Cosopt eye drops, 20 mg/mL + 5 mg/mL
Intervention type(s): Drug; Drug
Intervention description(s): Dosing schedule b.i.d.; Dosing schedule b.i.d.
Other intervention name(s): Dorzotimol; Cosopt
Intervention MeSH terms: Ophthalmic Solutions
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Glaucoma; Intraocular pressure; Treatment