Treatment of Ligneous Conjunctivitis in Children With Plasminogen Deficiency

This study will enroll one patient with recurrent ligneous conjunctivitis at University of Saskatchewan, Saskatchewan Health Authority in Saskatoon.

BACKGROUND:

Congenital plasminogen deficiency is an extremely rare autosomal recessive disorder that leads to formation of extravascular fibrin rich pseudomembranes in various organ systems including central nervous system, gastrointestinal, respiratory and otopharyngeal tracts (1, 2, 3). Conjunctival involvement in the form of recurrent woody growths underneath the eyelid (ligneous conjunctivitis) is the most common manifestation (5, 6). The symptoms are most severe in infants and children, where it may lead to central nervous system (CNS) hydrocephalus, respiratory failure or blindness, depending on the organ system involved (3,4)

The conjunctival pseudomembranes recur after excision and show a poor response to topical steroids, cyclosporine, or autologous serum administration. These lesions can lead to conjunctival scarring, ptosis, loss of visual acuity and ultimately blindness5,6.

Plasminogen replacement (in the form of topical drops of plasminogen concentrate or allogenic plasma) has proven to be the most effective modality in preventing growth of these lesions and is required by most patients to prevent end organ damage.

RATIONALE:

More than 200 cases of plasminogen deficiency have been reported in literature.(14) Plasminogen replacement (in the form of intraocular drops of plasminogen concentrate or donor plasma) has proven to be the most effective modality in preventing growth of these lesions and is required by most patients to prevent end organ damage (7-20).

Plasminogen concentrate is not an option as plasminogen concentrates are not available in Canada. There is one company that produces plasminogen concentrate in North America that is currently not supplying any products on compassionate basis and there are no open clinical trials. Another company (Kedrion) produces it in Italy though it is also not providing on compassionate basis. It is significantly cost prohibitive. Cost: 2800 Euros per ml of concentrate. The product needs to be applied to affected conjunctiva 3-8 times per day for \~3-12 months.

Heparin Therapy alone: Case report data shows utilization of Heparin therapy alone for ligneous conjunctivitis in children which led to orbital inflammation and cellulitis with only partial control of lesion (2).

Sustained control of these lesions has only been achieved with administration of plasminogen (Intravenous [IV]/local) or plasma (as a source of plasminogen) alone or in conjunction with other therapies (such as membrane resection, heparin etc (7-13), (15-20).

TRIAL OBJECTIVES AND PURPOSE:

1. Determine safety of topical administration of aliquoted allogeneic plasma to the affected eye.
2. Determine efficacy of topical administration of aliquoted allogenic plasma.

TRIAL TREATMENTS:

The allogenic plasma will be aliquoted into 3 ml aliquots and placed in 7 ml vials/bottles. The vials will be frozen at -18 degree Celsius or lower temperature. To administer, the vial/bottle will be warmed to room temperature (15-30 degree Celsius). 1-2 drops of aliquoted donor plasma will be administered to the affected eye every 1-5 hours per day daily at maximum. The administration of plasma drops can change in frequency based on the clinical assessment of ligneous conjunctivitis and response to therapy.

STUDY DURATION

The treatment administration period will be 2 to 6 months. The duration of study participation, including follow-up, will be approximately 24 months.

STUDY VARIABLES

The following data will be collected for this study:

1. Size of pseudomembranous conjunctival lesion
2. Visual acuity of the affected eye
3. Development of strabismus or other visual defects in affected eye
4. Medical history
5. Physical exam
6. Blood group (ABO, RhD) and antibody screen results
7. Details of any adverse events

All data will be collected on the data collection form. The participant's medical record will be considered to be a source document for the medical history. The lab report will be considered the source document for the lab tests.

STOPPING RULES AND DISCONTINUATION CRITERIA

Criteria for discontinuation

1. Patient does not want to continue the study
2. Patient has a significant adverse reaction to plasma drops

3. Patient has no response to therapy after 6 months of intervention. This is defined as:

   1. No change in the size of pseudomembranes after 6 months of topical allogenic plasma administration performed according to recommendations (with/without surgical excision)
   2. Increase in the size of pseudomembranous lesions despite recommended use of aliquoted allogenic plasma
   3. Development of new pseudomembranous lesions in the eye receiving topical allogenic plasma
4. More effective therapies (liquid plasminogen concentrate IV/Intra-ocular) become available in Canada
5. Plasma drops can no longer be provided

MONITORING OF PARTICIPANT COMPLIANCE

Participant compliance will be assessed by maintaining adequate drug dispensing logs and return records. Participants will be asked to return all unused study drug in the provided container at each visit as a measure of drug accountability and patient compliance.

ASSESSMENT OF SAFETY

Safety Parameters include:

1. Direct clinical monitoring of patient during initial 5 intra-ocular plasma administrations
2. Communication with the patient and family at least on a weekly basis while receiving intra-ocular plasma.
3. Source plasma collected from donors who are negative for transfusion transmissible infections
4. Source plasma cultured before release to facility to ensure no bacterial contamination
5. Clear guidance to parents about situations where plasma administration should be stopped, and clinical care accessed.
6. Communication to the pediatric hematology service available 24/7 in case of any issues with plasma administration
7. Close liaison with pediatric ophthalmologist who will also monitor response and potential complications

ADVERSE EVENTS and MITIGATION STRATEGIES

According to the ICH guideline for Good Clinical Practice, an adverse event is any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.

Serious Adverse Events

A serious adverse event is any adverse event that meets any of the following criteria:

1. Fatal (i.e., the adverse event actually causes or leads to death) 2. Life threatening (i.e., the adverse event, in the view of the investigator, places the patient at immediate risk of death). This does not include any adverse event that had it occurred in a more severe form, or was allowed to continue, might have caused death 3. Requires or prolongs inpatient hospitalization 4. Results in persistent or significant disability/incapacity (i.e., the adverse event results in substantial disruption of the patient's ability to conduct normal life functions) 5. Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to study drug 6. Significant medical event in the investigator's judgment (e.g., may jeopardize the patient or may require medical/surgical intervention to prevent one of the outcomes listed above). RISK MITIGATION STRATEGIES

1. Loss of patient privacy and confidentiality:

   1. All patient information will be recorded in hospital electronic medical record systems which have adequate protections in place to prevent unauthorized spread of patient information.
   2. The data collected for clinical trial will be maintained in University Operated Redcap which will be password protected and have access limited to the study personnel.

2. Serious or severe adverse reaction to topical applications of aliquoted plasma (irritation, inflammation, infection etc.)

   1. Initial few (\~3-5) topical administrations will be closely monitored in the hospital to assess for any adverse events with nursing and physician oversight.
   2. Patient/Family will be permitted to use the topical plasma independently at home only after 3-5 administrations have been monitored in hospital, parents are comfortable with storage and administration process and adverse events have been managed appropriately.
   3. In case of any adverse event such as irritation or inflammation etc. patient/family will be able to contact the responsible physician or their service at any time. Appropriate treatment strategies will be undertaken immediately for such events. Processes will be developed to prevent the adverse event from occurring in future if therapy can be continued and the event is non-fatal and non-life/limb threatening. All adverse events will be reported to the manufacturer (Canadian Blood Services).

STATISTICS

Statistical Methods Descriptive statistics for categorical and continuous variables will be used based on data points obtained and their distribution. Paired T test (or equivalent non-parametric test) will be used to determine difference in baseline and post intervention plasminogen levels at 4 weeks, 2 months, 3 months, 6 months till 24 months. A p-value of 0.05 will be considered significant. All data analyses will be conducted in Statistical software SAS version 9.4.

PLANNED PARTICIPANT ENROLLMENT One patient and 3 family members will be enrolled in this study currently. The rationale is that this is an extremely rare disorder with less than 5 patients in entire Canada and only one known patient in Saskatchewan.

DATA ACCOUNTABILITY Missing values will not be substituted by estimated values but will be treated as missing in the statistical evaluation. All data from patients randomised in the study will be included in all listings, plots, summary tables, and statistical analyses.