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The trial has terminated early due to the disruptions caused by the ongoing COVID-19 pandemic. The decision was not related to any efficacy, safety or clinical concerns regarding rVA576.
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Topical rVA576 for treatment of atopic keratoconjunctivitis (AKC), vernal keratoconjunctivitis (VKC),and severe allergic conjunctivitis (seasonal (SAC) or perennial (PAC)): a randomised placebo-controlled double masked parallel trial (TRACKER)
Recombinant rVA576 is a small protein (16.7kDa) which has two independent actions. It inhibits the activation and cleavage of complement C5 and it binds and inactivates leukotriene B4 (LTB4). It acts on the complement system by preventing the cleavage of C5 by C5 convertase into C5a and C5b and so is effective in inhibiting terminal complement activity irrespective of the activating pathway.
Atopic keratoconjunctivitis (AKC) is a type of allergic conjunctivitis which involves mast cell activation due to the predominance of inflammatory mediators such as eosinophils and Th2-generated cytokines (Mishra et al. 2011).
Recombinant rVA576 eye drops solution is the investigational medicinal product. It is intended for ophthalmic use by topical administration to the eye.
Recombinant rVA576 is a compact small protein molecule with a lipocalin-like structure consisting of alpha helices and a beta barrel. There is a surface-active site which binds to the complement C5 molecule with a high affinity (KD 1.85 x 10-8 M) and an internalised active site which binds the small eicosinoid molecule leukotriene B4 (Hepburn et al. 2007).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| rVA576 - Open-label period | Experimental | Part 1: The first 3 patients selected for the study will be treated with the active drug in an open-label manner at intervals of 1 week and will have weekly clinic visits until Day 14, after which the visit will be every two weeks. When the first 3 patients have completed two weeks of treatment and the safety and tolerability data has been reviewed by the PI and an independent clinician, provided the data is favourable the randomisation process will begin (Part 2). The first 3 patients will continue treatment for a total of 8 weeks and will be assessed throughout the trial by the Principal Investigator according to the Schedule of Events |
|
| Placebo - Double-blind period | Placebo Comparator | Part 2: Sixteen patients will be randomised 1:1. between active and placebo and patients allocated to either group will receive the appropriate product throughout the trial. |
|
| rVA576 - Double-blind period | Experimental | Part 2: Sixteen patients will be randomised 1:1. between active and placebo and patients allocated to either group will receive the appropriate product throughout the trial. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| rVA576 | Drug | Part 1: The first 3 patients selected for the study will be treated with the active drug in open-label. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Incidence of Ocular TEAE | Incidence of ocular treatment-emergent adverse events (TEAE) during the treatment period which have occurred during the 56 days following randomisation. | 56 days |
| Measure | Description | Time Frame |
|---|---|---|
| Post-instillation Comfort | Graded on patient diary cards at the intervals Day 1-14, 15-28, 29-42 and 43-56. Eye comfort scoring: 0 - Perfectly comfortable
The 14 day average score for each interval have been calculated for each patient (possible range of 0 to 40). Classifications were assigned using the average total score at each two week period as follows: < 10 = Comfortable/Acceptable, 10 - 19 = Moderately Uncomfortable, 20 - 29 = Very Uncomfortable, >= 30 = Severely/Unacceptably Uncomfortable. |
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Inclusion Criteria:
Aged 18 and above
Diagnosis of moderate to severe AKC, VKC, or severe allergic conjunctivitis (seasonal or perennial). Defined as:
Will have had received some topical therapy during the last 3 months without improvement but will not currently be receiving systemic immunotherapy. Topical therapy may be topical calcineurin inhibitors, antihistamines or corticosteroids alone or in combination. Lubricants or artificial tears will not a count as topical therapy for these purposes.
Will have had at least 7 days without topical ocular corticosteroids prior to entry
Willing to give informed consent
Willing to use highly effective contraceptive precautions for the duration of the study and for 90 days after the last dose of IMP
Willing to avoid prohibited medications for duration of study (see list of prohibited medications)
Exclusion Criteria:
Eye surface disease other than AKC, VKC or severe allergic conjunctivitis (SAC or PAC)
Contact lens use during the study
Complete or partial tarsorrhaphy. If such a procedure becomes necessary during the course of the trial patients may remain in the trial providing that at least 50% of the eye surface remains visible to slit lamp examination
Ankyloblepharon of any degree at entry to the trial
Known or suspected ocular malignancy
Active ocular infection at entry to the trial. Patients with eye surface bacterial, viral, fungal or protozoal infection may enter the trial after elimination of the infection as confirmed by eye swabs
Known or suspected uveitis
Participation in any other clinical trial within 1 month of enrolment
Use of any of the following prohibited medications:
Corneal perforation
Uncontrolled glaucoma (increase in dose of glaucoma medication or surgical intervention for glaucoma within 3 months prior to entry)
Pregnancy (females)
Breast feeding (females)
Known allergy to ticks or severe reaction to arthropod venom (e.g. bee or wasp venom)
Use of topical ocular steroids within 7 days of the Screening visit
Failure to satisfy the PI of suitability to participate for any other reason
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| Name | Affiliation | Role |
|---|---|---|
| Sajjad Ahmad | Moorfields Eye Hospital NHS Foundation Trust | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Hospital Clinic de Barcelona | Barcelona | Spain | ||||
| Instituto Universitario de Oftalmobiología Aplicada |
Patients in Part 1 did not continue into Part 2.
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| ID | Title | Description |
|---|---|---|
| FG000 | rVA576, Open-label Period (8 Weeks) | Part 1: The first three patients selected were treated with active drug in an open-label manner. They had weekly clinic visits for up the first two weeks and thereafter biweekly visits. When the third of the first three patients had completed their first two weeks of treatment, the PI reviewed the safety, tolerability, and ease of application for each patient before deciding to proceed to the randomised, double masked comparative phase of the study (Part 2). The three patients were to continue on the study and complete eight weeks of treatment as open-label patients. Patients in Part 1 did not continue into Part 2. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Open-label Period |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Feb 10, 2020 | Mar 14, 2022 |
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Randomised, double-masked, placebo-controlled parallel group comparison with open-label sentinel group.
| Placebo | Other | Part 2: Sixteen patients will be randomised 1:1. between active and placebo and patients allocated to either group will receive the appropriate product throughout the trial. |
|
| rVA576 | Drug | Part 2: Sixteen patients will be randomised 1:1. between active and placebo and patients allocated to either group will receive the appropriate product throughout the trial. |
|
|
| Day 1 to 56 |
| Visual Acuity | Visual acuity for the worst eye over time by Early Treatment Diabetic Retinopathy Study (ETDRS) charts comparison from Day 1 to Day 56 In ETDRS charts, zero indicates standard vision, positive values indicates poor vision, and negative values indicates good vision. | Day 1 to 56 |
| Clinical Scores | Change from Day 1 in composite clinical scores at Day 14, 28, 42 and 56, for the eye judged as worst affected at each visit. Score calculated from symptom and sign sub-components. AKC/VKC: symptom sub-component consisted of itch, tearing, discomfort, discharge, and photophobia, and the sign component consisted of bulbar conjunctival hyperaemia, tarsal conjunctival papillary hypertrophy, punctate keratitis, neovascularization of cornea, cicatrizing conjunctivitis, blepharitis. SAC/PAC: symptom sub-component consisted itch, tearing, discomfort, and photophobia, and the sign sub-component consisted of upper tarsal conjunctival hyperaemia, upper bulbar conjunctival hyperaemia, chemosis, upper tarsal conjunctival papillae, blepharitis. For each sign/symptom a score of 0 - 3 is awarded (0=absence of a sign/symptom; an increase in score indicates increase in severity). These scores are summed at the end of the exam to give the composite score. Range:0 to 33 (AKC/VKC) or 27 (SAC/PAC). | Day 1 to 56 |
| MMP-9 Positive | Percentage of patients with Matrix metalloprotease 9 (MMP-9) positive levels at Days 1, 28, and 56. MMP-9 is a is a nonspecific inflammatory marker. Detection was made using the Inflammadry® device. This device gives a binary (positive/negative) result. | Day 1 to 56 |
| Tear Film Break up Time | Change from Day 1 in Tear film break up time (TBUT) at Day 14, 28, 42 and 56. TBUT data was available for one eye only. Tear breakup time (TBUT) is a clinical test used to assess for evaporative dry eye disease. To measure TBUT, fluorescein is instilled into the patient's tear film and the patient is asked not to blink while the tear film is observed under a broad beam of cobalt blue illumination. The TBUT is recorded as the number of seconds that elapse between the last blink and the appearance of the first dry spot in the tear film. A TBUT under 10 seconds is considered abnormal. | Change from Day 1 at Day 14, 28, 42 and 56 |
| Valladolid |
| Spain |
| Bristol Eye Hospital | Bristol | United Kingdom |
| Addenbrookes Hospital | Cambridge | United Kingdom |
| St James's University Hospital | Leeds | United Kingdom |
| Royal Liverpool University Hospital | Liverpool | United Kingdom |
| Moorfields Eye Hospital NHS Foundation Trust | London | EC1V 2PD | United Kingdom |
| Royal Victoria Infirmary | Newcastle upon Tyne | United Kingdom |
| University Hospital NHS Foundation Trust | Southend-on-Sea | United Kingdom |
| FG001 | rVA576, Double-blind Period (8 Weeks) | Part 2: A randomised, double-masked, placebo controlled trial of topical rVA576, or placebo eye drops in moderate to severe AKC, VKC and severe allergic conjunctivitis (SAC or PAC). |
| FG002 | Placebo (8 Weeks) | Part 2: A randomised, double-masked, placebo controlled trial of topical rVA576, or placebo eye drops in moderate to severe AKC, VKC and severe allergic conjunctivitis (SAC or PAC). |
| COMPLETED |
|
| NOT COMPLETED |
|
|
| Randomized, Double-blind Period |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | rVA576, Open-label Period | Part 1: The first three patients selected were treated with active drug in an open-label manner. They had weekly clinic visits for up the first two weeks and thereafter biweekly visits. When the third of the first three patients had completed their first two weeks of treatment, the PI reviewed the safety, tolerability, and ease of application for each patient before deciding to proceed to the randomised, double masked comparative phase of the study (Part 2). The three patients were to continue on the study and complete eight weeks of treatment as open-label patients. |
| BG001 | rVA576, Double-blind Period | Part 2: A randomised, double-masked, placebo controlled trial of topical rVA576, or placebo eye drops in moderate to severe AKC, VKC and severe allergic conjunctivitis (SAC or PAC). |
| BG002 | Placebo | Part 2: A randomised, double-masked, placebo controlled trial of topical rVA576, or placebo eye drops in moderate to severe AKC, VKC and severe allergic conjunctivitis (SAC or PAC). |
| BG003 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | years |
| |||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
| ||||||||||||||||
| Race/Ethnicity, Customized | Count of Participants | Participants |
| ||||||||||||||||
| Indication | Count of Participants | Participants |
| ||||||||||||||||
| Patient group | Count of Participants | Participants |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Incidence of Ocular TEAE | Incidence of ocular treatment-emergent adverse events (TEAE) during the treatment period which have occurred during the 56 days following randomisation. | Posted | Count of Participants | Participants | 56 days |
|
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Secondary | Post-instillation Comfort | Graded on patient diary cards at the intervals Day 1-14, 15-28, 29-42 and 43-56. Eye comfort scoring: 0 - Perfectly comfortable
The 14 day average score for each interval have been calculated for each patient (possible range of 0 to 40). Classifications were assigned using the average total score at each two week period as follows: < 10 = Comfortable/Acceptable, 10 - 19 = Moderately Uncomfortable, 20 - 29 = Very Uncomfortable, >= 30 = Severely/Unacceptably Uncomfortable. | The Comfort score data was not available for one patient in the nomacopan group Part 2, and in one patient in Part 1, after Day 14, both due to withdrawal. Because only two patients in the Part 2 nomacopan group had data to assess comfort score, it is not meaningful to compare the nomacopan and placebo groups, and so further analysis was not performed. | Posted | Count of Participants | Participants | Day 1 to 56 |
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Secondary | Visual Acuity | Visual acuity for the worst eye over time by Early Treatment Diabetic Retinopathy Study (ETDRS) charts comparison from Day 1 to Day 56 In ETDRS charts, zero indicates standard vision, positive values indicates poor vision, and negative values indicates good vision. | Only one patient in the nomacopan group in Part 2 had data to assess this score. It is not meaningful to compare the nomacopan and placebo groups, and so further analysis was not performed. | Posted | Mean | Standard Deviation | Number of ETDRS letters | Day 1 to 56 |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Secondary | Clinical Scores | Change from Day 1 in composite clinical scores at Day 14, 28, 42 and 56, for the eye judged as worst affected at each visit. Score calculated from symptom and sign sub-components. AKC/VKC: symptom sub-component consisted of itch, tearing, discomfort, discharge, and photophobia, and the sign component consisted of bulbar conjunctival hyperaemia, tarsal conjunctival papillary hypertrophy, punctate keratitis, neovascularization of cornea, cicatrizing conjunctivitis, blepharitis. SAC/PAC: symptom sub-component consisted itch, tearing, discomfort, and photophobia, and the sign sub-component consisted of upper tarsal conjunctival hyperaemia, upper bulbar conjunctival hyperaemia, chemosis, upper tarsal conjunctival papillae, blepharitis. For each sign/symptom a score of 0 - 3 is awarded (0=absence of a sign/symptom; an increase in score indicates increase in severity). These scores are summed at the end of the exam to give the composite score. Range:0 to 33 (AKC/VKC) or 27 (SAC/PAC). | Because only two patients in the Part 2 nomacopan group had data to assess this score, it is not meaningful to compare the nomacopan and placebo groups, and so further analysis was not performed. Note there were two patients on Placebo with SAC; therefore, scored on a different scale compared to patients with AKC or VKC. For the purposes of the outcome measure, the SAC and AKC/VKC scores were combined to derive a single value across all participants. | Posted | Mean | Standard Deviation | score on a scale | Day 1 to 56 |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Secondary | MMP-9 Positive | Percentage of patients with Matrix metalloprotease 9 (MMP-9) positive levels at Days 1, 28, and 56. MMP-9 is a is a nonspecific inflammatory marker. Detection was made using the Inflammadry® device. This device gives a binary (positive/negative) result. | There were too few patients to make a meaningful interpretation. | Posted | Count of Participants | Participants | Day 1 to 56 |
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Secondary | Tear Film Break up Time | Change from Day 1 in Tear film break up time (TBUT) at Day 14, 28, 42 and 56. TBUT data was available for one eye only. Tear breakup time (TBUT) is a clinical test used to assess for evaporative dry eye disease. To measure TBUT, fluorescein is instilled into the patient's tear film and the patient is asked not to blink while the tear film is observed under a broad beam of cobalt blue illumination. The TBUT is recorded as the number of seconds that elapse between the last blink and the appearance of the first dry spot in the tear film. A TBUT under 10 seconds is considered abnormal. | Patient numbers within each treatment group are too small to make meaningful comparisons, and so no further analysis was performed. | Posted | Mean | Standard Deviation | seconds | Change from Day 1 at Day 14, 28, 42 and 56 |
|
From day 1 to day 56.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | rVA576, Open-label Period | Part 1: The first three patients selected were treated with active drug in an open-label manner. They had weekly clinic visits for up the first two weeks and thereafter biweekly visits. When the third of the first three patients had completed their first two weeks of treatment, the PI reviewed the safety, tolerability, and ease of application for each patient before deciding to proceed to the randomised, double masked comparative phase of the study (Part 2). The three patients were to continue on the study and complete eight weeks of treatment as open-label patients. | 0 | 3 | 0 | 3 | 3 | 3 |
| EG001 | rVA576, Double-blind Period | Part 2: A randomised, double-masked, placebo controlled trial of topical rVA576, or placebo eye drops in moderate to severe AKC, VKC and severe allergic conjunctivitis (SAC or PAC). | 0 | 3 | 0 | 3 | 2 | 3 |
| EG002 | Placebo | Part 2: A randomised, double-masked, placebo controlled trial of topical rVA576, or placebo eye drops in moderate to severe AKC, VKC and severe allergic conjunctivitis (SAC or PAC). | 0 | 6 | 0 | 6 | 3 | 6 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Atopic keratoconjunctivitis | Eye disorders | MedDRA | Systematic Assessment |
| |
| Keratitis | Eye disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Ocular hyperaemia | Eye disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Conjunctival hyperaemia | Eye disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Dry eye | Eye disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Eczema eyelids | Eye disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Eye discharge | Eye disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Eye pruritus | Eye disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Eye swelling | Eye disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Vision blurred | Eye disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Insomnia | Psychiatric disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Dry throat | Respiratory, thoracic and mediastinal disorders | MedDRA 21.1 | Systematic Assessment |
|
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Wynne H Weston-Davies | Akari | +44(0)7801 281283 | wynne.weston-davies@akaritx.com |
| Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Jul 12, 2021 | Mar 18, 2022 | SAP_001.pdf |
| ID | Term |
|---|---|
| D007637 | Keratoconjunctivitis |
| D003233 | Conjunctivitis, Allergic |
| ID | Term |
|---|---|
| D003231 | Conjunctivitis |
| D003229 | Conjunctival Diseases |
| D005128 | Eye Diseases |
| D007634 | Keratitis |
| D003316 | Corneal Diseases |
| D006969 | Hypersensitivity, Immediate |
| D006967 | Hypersensitivity |
| D007154 | Immune System Diseases |
Not provided
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| Male |
|
| Asian |
|
| White |
|
| Other |
|
| Vernal keratoconjunctivitis (VKC) |
|
| Seasonal allergic conjunctivitis (SAC) |
|
| Perennial allergic conjunctivitis (PAC) |
|
| SAC/PAC |
|
| Difference of percentage of participants |
| 33.3 |
| 2-Sided |
| 95 |
| -25.45 |
| 78.39 |
| Superiority |
| OG001 | rVA576, Double-blind Period | Part 2: A randomised, double-masked, placebo controlled trial of topical rVA576, or placebo eye drops in moderate to severe AKC, VKC and severe allergic conjunctivitis (SAC or PAC). |
| OG002 | Placebo | Part 2: A randomised, double-masked, placebo controlled trial of topical rVA576, or placebo eye drops in moderate to severe AKC, VKC and severe allergic conjunctivitis (SAC or PAC). |
|
|
| OG002 |
| Placebo |
Part 2: A randomised, double-masked, placebo controlled trial of topical rVA576, or placebo eye drops in moderate to severe AKC, VKC and severe allergic conjunctivitis (SAC or PAC). |
|
|
| OG001 | rVA576, Double-blind Period | Part 2: A randomised, double-masked, placebo controlled trial of topical rVA576, or placebo eye drops in moderate to severe AKC, VKC and severe allergic conjunctivitis (SAC or PAC). |
| OG002 | Placebo (AKC/VKC) | Part 2: A randomised, double-masked, placebo controlled trial of topical rVA576, or placebo eye drops in moderate to severe AKC or VKC |
| OG003 | Placebo (SAC/PAC) | Part 2: A randomised, double-masked, placebo controlled trial of topical rVA576, or placebo eye drops in moderate to severe AKC, VKC and severe allergic conjunctivitis (SAC or PAC). |
|
|
Part 2: A randomised, double-masked, placebo controlled trial of topical rVA576, or placebo eye drops in moderate to severe AKC, VKC and severe allergic conjunctivitis (SAC or PAC). |
|
|
Part 2: A randomised, double-masked, placebo controlled trial of topical rVA576, or placebo eye drops in moderate to severe AKC, VKC and severe allergic conjunctivitis (SAC or PAC).
| OG002 | Placebo | Part 2: A randomised, double-masked, placebo controlled trial of topical rVA576, or placebo eye drops in moderate to severe AKC, VKC and severe allergic conjunctivitis (SAC or PAC). |
|
|
| Moderately Uncomfortable |
|
| Moderately Uncomfortable |
|
| Moderately Uncomfortable |
|
| Title | Measurements |
|---|---|
|
| Title | Measurements |
|---|---|
|
| Title | Measurements |
|---|---|
|
| Title | Measurements |
|---|---|
|
| Negative |
|
| Negative |
|
| Negative |
|
| Negative |
|
| Negative |
|