Myopia Control With Novel Eye Drops
Condition: Myopia
MeSH terms: Myopia
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Myopia currently affects 30% of the world and by 2050, almost 50% of the world will be myopic
      based on conservative estimates.1 In 2050, this will equate to almost 5 billion people with
      myopia, and those with high myopia will total almost 1 billion.1 Due to the growing public
      health concerns surrounding myopia, including treatments for visual complications associated
      with high myopia, the resultant lost productivity and increased cost to society, a solution
      to ameliorate this issue is imperative.

      Current treatment strategies cannot prevent myopia, and their ability to slow myopia
      progression is variable, ranging from 10% to 59%.2 Based on the meta-analysis between the
      different interventions for myopia control, atropine eye-drops were proved the most effective
      strategy.3 Atropine has been used in myopia control treatment over the last 30 years in many
      countries with no serious adverse events reported.4-6 Moreover, atropine, a non-selective
      antimuscarinic agent, has been regularly applied in multiple other ocular conditions with
      respect to the official FDA approvals.7 8 Regarding the myopia management, recent studies
      show the significant effect of low dose atropine in controlling the progression of spherical
      equivalent with the least side-effects such as photophobia and blurry near vision.9 However,
      the lack of substantial data in reducing the axial growth rate of low dose atropine proposes
      a need of either using higher dose of atropine or in combination with other pharmaceutical
      agent having such the effect.

      We therefore aim to determine in a two-year clinical trial, the efficacy of the eye drops
      used in our clinical trial for its role in slowing progression of myopia.
    

Detailed description: 
      6.1. NULL HYPOTHESES

      There is no difference in the rate of progression of myopia as determined by change in
      spherical equivalent refractive error over time between PX using test eye drops compared to
      PX in the control arm.

      There is no difference in the rate of progression of myopia as determined by change in axial
      length over time between PX using test eye drops compared to PX in the control arm.

      6.2. DESCRIPTION Statistical analysis is planned to commence on completion of trial
      monitoring and the submission of the data analysis request form. Any interim analysis will be
      conducted as described in this section unless a documented request is received from the
      Sponsor and approved by the trial PI.

      Data stored in relational databases will be imported into SPSS / STATA software for
      statistical purposes. Data will be investigated for quality using range checks and frequency
      distribution. Underlying distributions of variables will be tested. In general, variables
      measured on an interval scale with a sufficiently large sample size will be considered to
      follow a normal distribution. Outputs from the statistical analysis such as statistical
      tables will be copied over to Excel. All statistical results will be reported in Excel
      format.

      6.3. NUMBER OF PARTICIPANTS Prior studies indicated that the annual progression of refractive
      error in Asian children using single-vision spectacles was -0.70 ± 0.45D. Thus approximately
      a minimum of 35 successfully enrolled subjects are required in each study group in order to
      demonstrate a statistically significant 50% difference in myopia progression (0.35 ± 0.45D)
      between test and control groups at the 5% level of significance with 80% power, using a
      2-tailed distribution and assuming 20% dropouts. The detectable difference of 0.35±0.45
      equates to an effect size of 0.78. G*power was used to compute the sample size.

      6.4. SIGNIFICANCE A p-value less than or equal to 5% will be considered to be statistically
      significant.

      6.5. INTERIM ANALYSIS The clinical trial will employ at least one interim analysis.
      Statistical adjustments to the level of significance for interim analysis will be based on an
      alpha spending function where the information fraction of the annual data at the time of the
      interim analysis will be multiplied by 5%. However, the interim analysis used to justify the
      need for study termination will set the statistical significance to 1%.

      6.6. ANALYSIS Participants who have commenced the clinical trial treatment will be included
      in the analysis dataset. Reasons and frequency distribution of participants discontinued at
      baseline will be reported. The analysis of efficacy variables such as subjective ratings will
      employ only scheduled and evaluable visits. The analysis of safety variables such as adverse
      responses will include all visits, including all unscheduled visits. The trial PI can request
      an analysis of only those participants who have completed the trial. The default type of
      analysis will follow an Intent-to-Treat principle. The analysis plan for each primary and
      secondary endpoint is described here.

      6.6.1. Primary Endpoint: Myopic progression using cycloplegic spherical equivalent Spherical
      equivalent will be recorded on an interval scale as obtained directly from the instrument.
      Progression of spherical equivalent defined as the change from baseline for each
      participant-eye will be computed and summarised as means ± standard deviations for each
      visit. Progression will be analysed using the intent to treat principle by linear mixed
      model. This model will account for the intra-subject correlation due to eye specific data and
      repeated visits by using subject random intercepts. The fixed effects will include treatment
      groups and visits. Subjects will be factored as random effects. The model will also include
      confounding demographic factors and baseline readings to obtain unbiased estimates. Estimated
      means and its confidence limits will be reported based on the model.

      Progression of spherical equivalent will also be converted to a binary format using a
      progression value such as -0.5D. Binary outcome variables will be analysed using logistic
      regression. Robust estimator of variance will be used to account for within subject
      correlation due to eye specific data.

      6.6.2. Secondary Endpoint: Myopic progression based on axial length change Axial length will
      be recorded on an interval scale as obtained directly from the respective instruments.
      Progression of axial length defined as the change from baseline for each participant-eye will
      be computed and summarised as means ± standard deviations for each visit. Progression in
      axial length will be analysed using the intent to treat principle by linear mixed model. This
      model will account for the intra-subject correlation due to eye specific data and repeated
      visits by using subject random intercepts. The fixed effects will include treatment groups
      and visits. Subjects will be factored as random effects. The model will also include
      confounding demographic factors and baseline readings to obtain unbiased estimates. Estimated
      means and its confidence limits will be reported based on the model.

      6.6.3. Adverse Events Adverse events will be recorded on a binary scale of 0 and 1, where 1
      denotes the incidence of a new event. Data will be summarised as incidence over
      participant-time and as a percentage of participant or participant-eyes. Incidence of the
      event over participant or participant-eyes will be compared between trial groups using
      logistic regression.

      6.6.4. Other Variables Data will be summarised as means ± standard deviations for variables
      measured on an interval scale and median ± interquartile range for ordinal variables and
      percentages for those that are categorical. Other commonly used tests of significance at each
      visit may include paired t-tests and group t-test for parametric data and Wilcoxon
      signed-rank test and rank sum test for non-parametric data. Test of other variables may also
      include Analysis of Variance (ANOVA) and repeated measures ANOVA to test for
      between-participant and within-participant factors. Test of other categorical variables may
      include McNemar's, Fisher's Exact and Chi-Square tests for within- and between-participant
      factors

      6.6.5. Statistical Adjustments Difference between trial groups will be ascertained at the
      baseline visit. If there are significant differences, the baseline value can be used as a
      covariate adjustment in the statistical model. Difference from baseline can also be computed
      and used for further statistical analysis. If the differences are statistically significant,
      but of low clinical significance, the analysis can be conducted without these adjustments.
      However, the clinical relevance of the baseline differences will be discussed with the trial
      PI.

      Simultaneous multiple group comparisons in a post-hoc analysis will be corrected using
      Bonferroni correction. No adjustments will be made for testing multiple endpoints such as
      multiple subjective ratings.

      6.6.6. Deviations from Statistical Plan The end of study analysis will be conducted as
      described in the protocol. Any changes to this plan will be documented in the data analysis
      request form and will need to be duly authorised by the study principal investigator. The
      data analysis request form will be retained along with other study documentation.

      6.7. SUB GROUP ANALYSIS The planned sub group analysis will be used only to investigate
      further hypotheses and not to make any conclusive inferences.

      6.8. CRITERIA FOR TERMINATION OF THE TRIAL FOR FINAL DATA ANALYSIS The trial will be
      terminated upon completion of the final visit by the last active participant or if any of the
      conditions of Section 6.4 (Participant Withdrawal) are met. An active participant is one who
      is enrolled in the clinical trial and has not been discontinued.

      6.9. PROTOCOL DEVIATION PROCESS AND ACCOUNTABILITY OF DATA

      The clinical trial team will bring deviations to the attention of the PI who, pending the
      significance of the deviation, will discuss with the Biostatistician, and with the Sponsor,
      as required.

      When applicable, at the end of each protocol, protocol deviations will be reviewed (masked)
      to determine whether any data should be excluded from the final analysis. A list of protocol
      deviations and a recommendation of the PI as to how to use the data collected at the
      respective visit will be given to the Sponsor for approval prior to data analysis.

      Individual datapoints that are missing will be excluded from analysis involving only those
      specific variables. A participant's complete visit data will not be excluded if some of the
      observations are missing. Data from unscheduled visits will be used only for adverse response
      analysis. Inclusion of outliers in the analysis will be based on the magnitude of change in
      test statistics with and without the outliers. Outliers will preferably be retained unless
      there is significant change in test results.

      The Clinical Ophthalmologist, in conjunction with the PI (Research Ophthalmologist), may
      label the clinic visit as "non evaluable" on any deviations as deemed appropriate. This would
      then be used to exclude the clinical trial visit from the analysis. Any other
      variable-specific exclusion will be listed in the analysis request form and approved by the
      trial PI.

      A list is generated of all protocol deviations reported, and this information and any
      subsequent analysis and comment, is included in the final "Clinical Investigation - End of
      Clinical trial Report".

      QUALITY CONTROL AND QUALITY ASSURANCE 7.1. CRTC MONITORING A monitor will ensure all
      essential documents are in place prior to study commencement and that all participants have
      signed the participant informed consent form prior to any study procedures being performed.
      No other monitoring will be performed due to the scale of the project.

      7.2. PROTOCOL AMENDMENTS Protocol amendments will be submitted to the Sponsor and HREC for
      review and approval prior to implementation, unless the change required is to eliminate an
      immediate hazard to participants, or involves only administrative and/or logistical aspects
      of the studies (e.g. change in contact numbers).

      7.3. PROTOCOL DEVIATIONS The Investigator will not deviate from the protocol except if the
      deviation affects Participants' rights, safety and well-being. Any deviation from the
      protocol shall be recorded together with an explanation, including corrective and preventive
      actions and reported to the required bodies within the specified timeframe. The Sponsor is
      responsible for analysing and assessing the significance of the deviation and determining if
      data will be excluded.

      7.4. MAINTENANCE AND CALIBRATION OF EQUIPMENT Equipment will be monitored regularly for
      maintenance and calibration as per relevant Institute / CRTC SOPs, company and product
      manuals.

      ETHICAL CONSIDERATIONS The protocols require HREC approval prior to start and will be
      conducted as per the applicable regulatory requirements.

      The Investigator is to ensure that the protocol, PI/ICF, Investigator Brochure, available
      safety information, information about payment and compensation to participants, advertising
      or any clinical trial-specific information provided to participants (including potential
      participants), the Investigator's CV and/or evidence of appropriate qualifications and any
      other documentation they may request are submitted, reviewed and approved by the HREC. Any
      subsequent amendments will be reviewed and approved by an HREC prior to implementation.

      8.1. CONFIDENTIALITY Confidentiality will be maintained throughout the studies by all parties
      involved in accordance with guidelines under Section 95 of the Privacy Act 1998, and
      guidelines approved under Section 95a of the Privacy Act 1998 (December 2001). Data will be
      secured against unauthorised access.

      Privacy and confidentiality of information about each participant will be preserved in the
      reports and any publication of the clinical trial data.

      8.2. INFORMED CONSENT The informed consent process and documentation to be used for the trial
      will be reviewed and approved by the HREC prior to use.

      The informed consent process provides the participant with ongoing explanations that will
      allow them to make educated decisions about whether to begin or continue participating in the
      trial. The Investigator will discuss the trial with the participant and the participant will
      have the opportunity to ask questions before, during and after the trial. The participant
      will be informed that at any time during their involvement in the trial, they have the
      opportunity to withdraw this consent.

      The PI/ICF provides a summary of the trial, including its purpose, procedures and schedule,
      potential risks and benefits, and alternative treatments. It also explains the participant's
      rights once in the trial. The participant is given sufficient time to consider whether or not
      to participate and if they agree to voluntarily take part, they give their consent by signing
      the PI/ICF.
    

Intervention name(s): BHVI1 eye drops; BHVI2 eye drops; BHVI3 eye drops
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Including 35 children enrolled to receive BHVI1 eye-drops once nightly; Including 35 children enrolled to receive BHVI2 eye-drops once nightly; Including 35 children enrolled to receive BHVI3, combination of BHVI1 and BHVI2, eye-drops once nightly
Other intervention name(s): Novel BHVI1 eye drops; Novel BHVI2 eye drops; Novel BHVI3 eye drops
Intervention MeSH terms: Ophthalmic Solutions
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: In the intervention group, there will be a minimum of 105 participants enrolled with the participants randomised to 3 groups of 35 in each group to receive either BHVI1, BHVI2 , or BHVI3 per group.
In the non-randomized, matched control group, there will be 105 other participants recruited with similar inclusion and exclusion criteria and similar procedures as outlined but without any eye drops.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Atropine; Combination eye drops; Myopia control