Trial Outcomes & Findings for COSOPT-S® Treatment Versus Acetazolamide Before Trabeculectomy (NCT NCT01228149)

Last Updated: 2017-08-01

Results Overview

Change in IOP (ΔIOP) three months after trabeculectomy in comparison to the mean preoperative IOP at one day prior surgery

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

62 participants

Primary outcome timeframe

12 weeks

Results posted on

2017-08-01

Participant Flow

Participant milestones

Participant milestones
Measure	Diamox/DexaEDO Patients receive oral acetazolamide starting 28 days preoperatively. 7 days preoperatively dexamethasone eyedrops without preservatives are applied additionally. Trabeculectomy: Filtrating glaucoma surgery, preoperative treatment will be assessed.	Cosopt S Patients receive Cosopt S eye drops starting 28 days preoperatively Trabeculectomy: Filtrating glaucoma surgery, preoperative treatment will be assessed.
Overall Study STARTED	32	30
Overall Study COMPLETED	27	26
Overall Study NOT COMPLETED	5	4

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

COSOPT-S® Treatment Versus Acetazolamide Before Trabeculectomy

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Diamox/DexaEDO n=32 Participants Patients receive Diamox (oral acetazolamide) starting 28 days preoperatively. 7 days preoperatively DexaEDO (dexamethasone) eyedrops without preservatives are applied additionally. Trabeculectomy: Filtrating glaucoma surgery, preoperative treatment will be assessed.	Cosopt S n=30 Participants Patients receive Cosopt S (dorzolamide/timolol) eye drops starting 28 days preoperatively Trabeculectomy: Filtrating glaucoma surgery, preoperative treatment will be assessed.	Total n=62 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	17 Participants n=5 Participants	12 Participants n=7 Participants	29 Participants n=5 Participants
Age, Categorical >=65 years	15 Participants n=5 Participants	18 Participants n=7 Participants	33 Participants n=5 Participants
Age, Continuous	64.2 years STANDARD_DEVIATION 10.51 • n=5 Participants	65.8 years STANDARD_DEVIATION 8.82 • n=7 Participants	64.98 years STANDARD_DEVIATION 9.68 • n=5 Participants
Sex: Female, Male Female	19 Participants n=5 Participants	12 Participants n=7 Participants	31 Participants n=5 Participants
Sex: Female, Male Male	13 Participants n=5 Participants	18 Participants n=7 Participants	31 Participants n=5 Participants
Region of Enrollment Germany	32 Participants n=5 Participants	30 Participants n=7 Participants	62 Participants n=5 Participants

PRIMARY outcome

Timeframe: 12 weeks

Population: In total 62 patients were randomized, 30 to COSOPT-S®, 32 to DIAMOX+Dexa edo® (intention-to-treat (ITT) population. Per-protocol (PP) population (treated \>8 days and did not take any medication that interfered with the study): n=58 patients: 27 p. in COSOPT-S®, 31 p. in DIAMOX+Dexa edo®. Analysis population: patients who completed the study n=53

Change in IOP (ΔIOP) three months after trabeculectomy in comparison to the mean preoperative IOP at one day prior surgery

Outcome measures

Outcome measures
Measure	Diamox/DexaEDO n=27 Participants Patients receive oral Diamox (acetazolamide) starting 28 days preoperatively. 7 days preoperatively DexaEDO (dexamethasone) eyedrops without preservatives are applied additionally. Trabeculectomy: Filtrating glaucoma surgery, preoperative treatment will be assessed.	Cosopt S n=26 Participants Patients receive Cosopt S (dorzolamide/timolol) eye drops starting 28 days preoperatively Trabeculectomy: Filtrating glaucoma surgery, preoperative treatment will be assessed.
Change in Intraocular Pressure (IOP) (ΔIOP) Three Months After Trabeculectomy in Comparison to the Mean Preoperative IOP	8.30 mmHg Interval 6.85 to 9.75	8.12 mmHg Interval 6.67 to 9.58

SECONDARY outcome

Timeframe: 12 weeks

Population: Patients of the PP population

number of patients requirering needling

Outcome measures

Outcome measures
Measure	Diamox/DexaEDO n=31 Participants Patients receive oral Diamox (acetazolamide) starting 28 days preoperatively. 7 days preoperatively DexaEDO (dexamethasone) eyedrops without preservatives are applied additionally. Trabeculectomy: Filtrating glaucoma surgery, preoperative treatment will be assessed.	Cosopt S n=27 Participants Patients receive Cosopt S (dorzolamide/timolol) eye drops starting 28 days preoperatively Trabeculectomy: Filtrating glaucoma surgery, preoperative treatment will be assessed.
Number of Needling	0 Participants	2 Participants

SECONDARY outcome

Timeframe: 12 weeks

Population: PP Population (n=58)

Number of post-operative necessary 5-Fluorouracil (5FU) injections at week 12

Outcome measures

Outcome measures
Measure	Diamox/DexaEDO n=31 Participants Patients receive oral Diamox (acetazolamide) starting 28 days preoperatively. 7 days preoperatively DexaEDO (dexamethasone) eyedrops without preservatives are applied additionally. Trabeculectomy: Filtrating glaucoma surgery, preoperative treatment will be assessed.	Cosopt S n=27 Participants Patients receive Cosopt S (dorzolamide/timolol) eye drops starting 28 days preoperatively Trabeculectomy: Filtrating glaucoma surgery, preoperative treatment will be assessed.
Number of Necessary 5-Fluorouracil (5FU) Injections	5.14 number of injections Standard Deviation 2.61	5.26 number of injections Standard Deviation 3.13

SECONDARY outcome

Timeframe: 24 weeks

Population: PP Population

Ocular hypotension rate (0-5 mmHg of the study eye) indicated by the number of patients with ocular hypertension

Outcome measures

Outcome measures
Measure	Diamox/DexaEDO n=31 Participants Patients receive oral Diamox (acetazolamide) starting 28 days preoperatively. 7 days preoperatively DexaEDO (dexamethasone) eyedrops without preservatives are applied additionally. Trabeculectomy: Filtrating glaucoma surgery, preoperative treatment will be assessed.	Cosopt S n=27 Participants Patients receive Cosopt S (dorzolamide/timolol) eye drops starting 28 days preoperatively Trabeculectomy: Filtrating glaucoma surgery, preoperative treatment will be assessed.
Ocular Hypotension Rate	5 Participants	3 Participants

SECONDARY outcome

Timeframe: 28 days

Population: PP Population

Change in IOP between Visit 1 (Screening visit 16 to 28 day prior trabeculectomy) and Visit 2 (1 day before trabeculectomy). Outcome shows mean of differences and 95% confidence intervall.

Outcome measures

Outcome measures
Measure	Diamox/DexaEDO n=31 Participants Patients receive oral Diamox (acetazolamide) starting 28 days preoperatively. 7 days preoperatively DexaEDO (dexamethasone) eyedrops without preservatives are applied additionally. Trabeculectomy: Filtrating glaucoma surgery, preoperative treatment will be assessed.	Cosopt S n=27 Participants Patients receive Cosopt S (dorzolamide/timolol) eye drops starting 28 days preoperatively Trabeculectomy: Filtrating glaucoma surgery, preoperative treatment will be assessed.
Change in IOP Between Visit 1 and 2	8.19 mmHg Interval 5.77 to 10.61	1.88 mmHg Interval -0.59 to 4.34

SECONDARY outcome

Timeframe: 24 weeks

Population: PP Population

Filtration bleb classification (Grehn) in both Groups 1 week, 4 weeks, 12 weeks and 24 week after surgery. For classification the following criteria were evaluated and scored as described below: * vascularisation (0=None, 1=mild, 2=a few corkscrew vessels) * identifiability (0=no borders to sides; 1=demarcation nasally or temporally; 2= demarcation to both sides; 3= encapsulated) * Thickness (0= a least 3mm; 1=2mm; 2= 1mm; 3=flat) * Microcysts (0=no; 1= yes) * Transparency (0= highly transparent; 2=moderate; 2=not transparent) * Mobility (0= yes; 1= no) * Leakage (0=yes, 1=no) For the change in the filtration bleb classification (only thickness at visit 5/week 12 mentioned below) descriptive statistics were presented only.

Outcome measures

Outcome measures
Measure	Diamox/DexaEDO n=31 Participants Patients receive oral Diamox (acetazolamide) starting 28 days preoperatively. 7 days preoperatively DexaEDO (dexamethasone) eyedrops without preservatives are applied additionally. Trabeculectomy: Filtrating glaucoma surgery, preoperative treatment will be assessed.	Cosopt S n=27 Participants Patients receive Cosopt S (dorzolamide/timolol) eye drops starting 28 days preoperatively Trabeculectomy: Filtrating glaucoma surgery, preoperative treatment will be assessed.
Filtration Bleb Classification 2 mm	14 Participants	17 Participants
Filtration Bleb Classification 1 mm	5 Participants	5 Participants
Filtration Bleb Classification Flat	3 Participants	2 Participants
Filtration Bleb Classification Missing	5 Participants	1 Participants
Filtration Bleb Classification at least 3 mm	4 Participants	2 Participants

SECONDARY outcome

Timeframe: 12 weeks

Population: ITT Population

Change in quality of life measure by a certified National Eye Institute Visual Functioning Questionnaire containing 25 questions (NEI VFQ-25).Patients tick a score at every question to present their visual functioning (usually from 1-5 or 1-6 in which 1 is best and 6 worse). Every single item/score is transformed to a scale between 0 and 100 (0 best, 100 worse). For the total score, the mean of all transformed scores/items is calculated. NEI VFQ 25 Quality of Life Questionnaire composite score at V5 (week 12 after surgery). Outcome shows mean of differences and 95% confidence intervall.

Outcome measures

Outcome measures
Measure	Diamox/DexaEDO n=32 Participants Patients receive oral Diamox (acetazolamide) starting 28 days preoperatively. 7 days preoperatively DexaEDO (dexamethasone) eyedrops without preservatives are applied additionally. Trabeculectomy: Filtrating glaucoma surgery, preoperative treatment will be assessed.	Cosopt S n=30 Participants Patients receive Cosopt S (dorzolamide/timolol) eye drops starting 28 days preoperatively Trabeculectomy: Filtrating glaucoma surgery, preoperative treatment will be assessed.
Change in Quality of Life	80.71 scores on a scale Standard Deviation 11.64	79.48 scores on a scale Standard Deviation 15.44

SECONDARY outcome

Timeframe: 24 weeks

Population: ITT population

Conjunctival redness (ORA Scale) evaluated from 16 up to 28 days (time window) prior surgery and 1 day prior surgery. The investigator compares patient's study eye with a set of reference photos showing various degrees of redness. Redness was scored on a scale of "none", "mild", "moderate", "severe" and "very severe". Absolute and relative frequencies of visit 1 and 2 were compared descriptively.

Outcome measures

Outcome measures
Measure	Diamox/DexaEDO n=32 Participants Patients receive oral Diamox (acetazolamide) starting 28 days preoperatively. 7 days preoperatively DexaEDO (dexamethasone) eyedrops without preservatives are applied additionally. Trabeculectomy: Filtrating glaucoma surgery, preoperative treatment will be assessed.	Cosopt S n=30 Participants Patients receive Cosopt S (dorzolamide/timolol) eye drops starting 28 days preoperatively Trabeculectomy: Filtrating glaucoma surgery, preoperative treatment will be assessed.
Change in Conjunctival Redness Visit 1 · none	1 Participants	0 Participants
Change in Conjunctival Redness Visit 1 · mild	13 Participants	12 Participants
Change in Conjunctival Redness Visit 1 · moderate	13 Participants	15 Participants
Change in Conjunctival Redness Visit 1 · severe	4 Participants	3 Participants
Change in Conjunctival Redness Visit 1 · very severe	1 Participants	0 Participants
Change in Conjunctival Redness Visit 2 · none	9 Participants	7 Participants
Change in Conjunctival Redness Visit 2 · mild	15 Participants	16 Participants
Change in Conjunctival Redness Visit 2 · moderate	2 Participants	4 Participants
Change in Conjunctival Redness Visit 2 · severe	1 Participants	0 Participants
Change in Conjunctival Redness Visit 2 · very severe	0 Participants	0 Participants

SECONDARY outcome

Timeframe: week 12

Population: Intention-to- treat population

Number of suture lyses at visit 5 (week 12 after surgery)

Outcome measures

Outcome measures
Measure	Diamox/DexaEDO n=32 Participants Patients receive oral Diamox (acetazolamide) starting 28 days preoperatively. 7 days preoperatively DexaEDO (dexamethasone) eyedrops without preservatives are applied additionally. Trabeculectomy: Filtrating glaucoma surgery, preoperative treatment will be assessed.	Cosopt S n=30 Participants Patients receive Cosopt S (dorzolamide/timolol) eye drops starting 28 days preoperatively Trabeculectomy: Filtrating glaucoma surgery, preoperative treatment will be assessed.
Number of Suture Lyses 3-4 suture lyses	7 Participants	5 Participants
Number of Suture Lyses 0 suture lyses	11 Participants	10 Participants
Number of Suture Lyses 1-2 suture lyses	10 Participants	12 Participants

Adverse Events

Diamox/DexaEDO

Serious events: 4 serious events

Other events: 30 other events

Deaths: 0 deaths

Cosopt S

Serious events: 3 serious events

Other events: 23 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Diamox/DexaEDO n=31 participants at risk Patients receive Diamox (oral acetazolamide) starting 28 days preoperatively. 7 days preoperatively DexaEDO (dexamethasone) eyedrops without preservatives are applied additionally. Trabeculectomy: Filtrating glaucoma surgery, preoperative treatment will be assessed.	Cosopt S n=28 participants at risk Patients receive Cosopt S (dorzolamide/timolol) eye drops starting 28 days preoperatively Trabeculectomy: Filtrating glaucoma surgery, preoperative treatment will be assessed.
Cardiac disorders Cardiac disorders	3.2% 1/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	0.00% 0/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Eye disorders Iris incaceration	0.00% 0/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	3.6% 1/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Eye disorders Iris neovascularisation	3.2% 1/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	0.00% 0/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Injury, poisoning and procedural complications Meniscus injury	0.00% 0/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	3.6% 1/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Investigations Intraocular pressure increased	3.2% 1/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	0.00% 0/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Investigations Musculoskeletal and connective tissue	0.00% 0/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	3.6% 1/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Investigations Osteoarthritis	0.00% 0/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	3.6% 1/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Neoplasm skin	3.2% 1/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	0.00% 0/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Surgical and medical procedures Haemorrhoid operation	0.00% 0/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	3.6% 1/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.

Other adverse events

Additional Information

Dr. Dr. Katrin Lorenz

Dept. of Ophthalmology, University Medical Center Mainz

Phone: 00496131174069

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Diamox/DexaEDO n=31 participants at risk Patients receive Diamox (oral acetazolamide) starting 28 days preoperatively. 7 days preoperatively DexaEDO (dexamethasone) eyedrops without preservatives are applied additionally. Trabeculectomy: Filtrating glaucoma surgery, preoperative treatment will be assessed.	Cosopt S n=28 participants at risk Patients receive Cosopt S (dorzolamide/timolol) eye drops starting 28 days preoperatively Trabeculectomy: Filtrating glaucoma surgery, preoperative treatment will be assessed.
Eye disorders Visual acuity reduced	48.4% 15/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	53.6% 15/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Nervous system disorders Paraesthesia	45.2% 14/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	0.00% 0/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Nervous system disorders Headache	9.7% 3/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	7.1% 2/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Gastrointestinal disorders Abdominal pain upper	16.1% 5/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	0.00% 0/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Injury, poisoning and procedural complications Foreign body in eye	0.00% 0/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	3.6% 1/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Cardiac disorders Atrial faibrillation	3.2% 1/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	0.00% 0/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Investigations Weight decreased	6.5% 2/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	0.00% 0/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Respiratory, thoracic and mediastinal disorders Dyspnoea	12.9% 4/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	0.00% 0/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Vascular disorders Blood pressure fluctuation	3.2% 1/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	0.00% 0/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Psychiatric disorders Anxietry disorder	0.00% 0/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	3.6% 1/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Musculoskeletal and connective tissue disorders Intervertebral disc protrusion	0.00% 0/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	3.6% 1/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Infections and infestations Conjunctivitis bacterial	3.2% 1/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	0.00% 0/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Reproductive system and breast disorders Benign prostatic hyperplasia	0.00% 0/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	3.6% 1/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Skin and subcutaneous tissue disorders Alopecia	3.2% 1/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	3.6% 1/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Metabolism and nutrition disorders Hypokalaemia	3.2% 1/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	0.00% 0/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) neoplasm skin	3.2% 1/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	0.00% 0/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Injury, poisoning and procedural complications Eye operation complication	16.1% 5/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	14.3% 4/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Eye disorders Corneal epithelial defect	22.6% 7/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	0.00% 0/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Eye disorders erythema of eyelid	6.5% 2/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	14.3% 4/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Eye disorders corneal erosion	6.5% 2/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	10.7% 3/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Eye disorders eyelid oedema	9.7% 3/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	3.6% 1/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Investigations intraocular pressure increased	12.9% 4/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	0.00% 0/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Eye disorders corneal defect	6.5% 2/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	3.6% 1/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Eye disorders conjunctival haemmorrhage	3.2% 1/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	7.1% 2/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Eye disorders eye irritation	3.2% 1/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	7.1% 2/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Eye disorders Hyphaema	9.7% 3/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	0.00% 0/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Eye disorders Blepharitis	0.00% 0/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	3.6% 1/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Eye disorders Choroidal detachment	3.2% 1/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	0.00% 0/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Eye disorders Conjunctival hyperaemia	19.4% 6/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	3.6% 1/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Eye disorders Conjunctivitis	0.00% 0/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	3.6% 1/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Eye disorders Corneal oedema	3.2% 1/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	0.00% 0/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Eye disorders Foreign body sensation in eye	0.00% 0/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	3.6% 1/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Eye disorders Iris incaeceration	0.00% 0/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	7.1% 2/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Eye disorders Iris Neovascularization	3.2% 1/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	0.00% 0/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Eye disorders Keratitis	0.00% 0/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	3.6% 1/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Eye disorders Lacrimation increased	0.00% 0/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	3.6% 1/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Eye disorders Macular oedema	3.2% 1/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	0.00% 0/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Eye disorders Scleral haemorrhage	0.00% 0/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	3.6% 1/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Nervous system disorders Dizziness	22.6% 7/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	7.1% 2/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Nervous system disorders Dysgeusia	32.3% 10/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	0.00% 0/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Nervous system disorders Hypoaesthesia	6.5% 2/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	0.00% 0/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Nervous system disorders Migraine	3.2% 1/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	0.00% 0/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Gastrointestinal disorders Diarrhoea	12.9% 4/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	0.00% 0/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Gastrointestinal disorders Flatulence	6.5% 2/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	0.00% 0/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Gastrointestinal disorders Nausea	25.8% 8/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	3.6% 1/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Gastrointestinal disorders Vomiting	3.2% 1/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	0.00% 0/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
General disorders Drug intolerance	0.00% 0/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	3.6% 1/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
General disorders Fatigue	41.9% 13/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	7.1% 2/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Injury, poisoning and procedural complications Meniscus injury	0.00% 0/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	3.6% 1/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Cardiac disorders Coronary artery disease	3.2% 1/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	0.00% 0/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Cardiac disorders Palpitations	12.9% 4/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	0.00% 0/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Cardiac disorders Tachycardia	3.2% 1/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	0.00% 0/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Psychiatric disorders Depressed mood	3.2% 1/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	0.00% 0/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Psychiatric disorders Depression	3.2% 1/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	0.00% 0/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Psychiatric disorders Insomnia	3.2% 1/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	0.00% 0/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Psychiatric disorders Nervousness	3.2% 1/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	0.00% 0/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Vascular disorders Hypertension	3.2% 1/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	7.1% 2/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Infections and infestations Fungal infection	3.2% 1/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	0.00% 0/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Infections and infestations Nasopharyngitis	3.2% 1/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	0.00% 0/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Musculoskeletal and connective tissue disorders Osteoarthritis	0.00% 0/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	3.6% 1/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Musculoskeletal and connective tissue disorders Pain in extremity	0.00% 0/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	3.6% 1/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Reproductive system and breast disorders Uterine polyp	3.2% 1/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	0.00% 0/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.
Surgical and medical procedures Haemorrhoid operation	0.00% 0/31 Adverse Event data were colleted from patients with at least one documented treatment with study drug.	3.6% 1/28 Adverse Event data were colleted from patients with at least one documented treatment with study drug.