• Amendment #1, Version 2.0, dated 21 April 2010: This amendment made 2 minor modifications in clinical procedures that enhanced feasibility and subject safety without affecting the efficacy objectives of the trial: o First, the type of tonometer was no longer limited to a single instrument, so that the protocol was more readily implemented at multiple sites. Since each subject served as his/her own control for tonometry measurements over the course of the trial, and since the same tonometer was always to be used within any given study site, intra-ocular pressure data analyses would not be affected. o Second, for purposes of safety monitoring, visual field (VF) testing was added at Week 8, and corneal pachymetry was added at Weeks 8 and 16. o This amendment also modified the inclusion criteria to further enhance subject safety by eliminating from consideration potential enrollees who would have had to discontinue previously efficacious ocular anti-hypertensive medication to qualify for the trial.

• Amendment #2, Version 3.0, dated 24 May 2010: This amendment clarified the Exclusion Criteria by removing redundancy and introducing more precision about which patient population certain criteria applied to. o The Exclusion Criterion reading “Mean VF pattern standard deviation (PSD), on reliable testing, of ≥2.0 dB in either eye” was removed because it was applicable only to patients with ocular hypertension, who were already well defined in Inclusion Criterion #1.a and Exclusion Criterion #5 (in this amendment); and contradicted Inclusion Criterion #1.b, because most glaucoma patients have a mean VF PSD of >2.0 dB. It was therefore removed because it was redundant and potentially confusing. o The Exclusion Criterion relating to “advanced VF defect in either eye” (Exclusion Criterion #4 in this amendment) was modified to refer specifically to patients with glaucoma, because it was not relevant to patients with ocular hypertension. Likewise, the Exclusion Criterion relating to the “Ocular Hypertension Treatment Study Group and European Glaucoma Prevention Study Group Primary Open-Angle Glaucoma Risk Table” (Exclusion Criterion #5 in this amendment) was modified to refer specifically to patients with ocular hypertension, because it is used only in this population to stratify risk. o In sum, these changes were made to ensure consistency of patient population definitions and application of the entry criteria, and did not impact upon patient safety. o Additional editorial changes were made to clarify screening and inclusion procedures and details of selected ophthalmologic examinations. None altered the nature or the conduct of the protocol.

• Amendment #3, Version 4.0, dated 15 February 2011 (Israel only): The purpose of this amendment was to specify the expected enrollment in the 2 countries involved in this trial for informational and regulatory purposes. There were no changes to any protocol procedures, and patient safety was not affected.

• Amendment #4, Version 5.0, dated 03 July 2012: The purpose of this amendment was to specify the 3 countries involved in this trial for informational and regulatory purposes and allow the enrollment of a more representative patient population without compromising the trial’s safety or efficacy objectives.

• Amendment #5, Version 6.0, dated 03 January 2013: The purpose of this Amendment was to facilitate protocol enrollment and operations, without affecting subject risk. Since both ophthalmologists and patients were accustomed to treating elevated IOP and glaucoma with available therapies, it had been difficult to enroll untreated patients under the original protocol entry criteria, despite the rigorous safety incorporated into the trial. These original criteria excluded concomitant ocular hypotensive treatments, in an attempt to isolate the pharmacologic activity of CF101 monotherapy in this population. Amendment 5 allowed CF101 to be used in combination with standard topical regimens, and was therefore expected to facilitate enrollment without interfering with the efficacy objectives of the trial. In recognition of the fact that subjects would now enter the trial already receiving standard ocular hypotensive therapy, the minimum entry IOP was reduced from 24 to 22 mmHg. Since the sample size calculation was based not on absolute IOP values but on relative differences between active and placebo groups, no change in sample size was necessary. Amendment 5 also made several minor editorial and administrative modifications and clarifications, reconciled the use of “subject” and “patient”, and removed the names of participating countries to allow for flexibility.

• Amendment #6, Version 7.0, dated 20 May 2013: At the request of study sites, the sponsor clarified the examination procedures.

• Amendment #7, Version 8.0, dated 23 June 2014: The initial rationale for this clinical trial is described in protocol Section 6.6. Since the launch of CF101-231GL, the Sponsor completed enrollment in protocol CF101-301KCS, a Phase 3 trial in 237 subjects with keratoconjunctivitis sicca. Analysis of IOP data from that trial indicated that the 1 mg BID dose of CF101 was less effective in reducing IOP than initially found in protocol CF101-201KCS (see protocol Section 6.6). It should be noted that in that trial, all enrolled subjects were ocularly normotensive, and that IOP was measured as a safety, not an efficacy, assessment. Thus, even though Segment 1 of the current trial had not completed or been reviewed by the planned Data Review Committee, there were data from an external source strongly suggesting that a higher dose range of CF101 needed to be explored in subjects with elevated IOP. Therefore, this Amendment did the following: o Eliminated the possibility of a CF101 0.1 mg dose group, based on data suggesting this dose will be too low to be effective; o Formalized the CF101 2.0 mg dose group, to explore a higher and perhaps more efficacious dose level and to better define the dose-range of CF101 in this patient population; and o Eliminated the requirement for the Data Review Committee, as no new dosing decisions would have to be made based on current knowledge. o Given existing and accumulating data from Phase 2 trials in other indications (see current Clinical Investigator Brochure), no new risks to subjects are anticipated from the dosing changes proposed in this Amendment.