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The purpose of the study is to determine whether topical ocular administration of LME636 60 mg/mL is efficacious in resolving the ocular inflammation in the anterior chamber (AC) associated with acute anterior uveitis (AAU).
Eligible subjects will be randomized to LME636 or Dexamethasone in a 3:1 ratio at the time they present to the trial site with the AAU flare and will enter treatment for 28 full days. Subjects with worsening disease from Visit 2/Day 4 onward or subjects without improvement after 14 days of treatment will be discontinued from treatment, unmasked and treated with a rescue regimen at the discretion of the investigator.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| LME636 | Experimental | LME636 60 mg/mL ophthalmic solution, maximum drop frequency administered for 2 weeks, followed by a tapering for 1 week (Week 3) and 1 week of masked Vehicle administration (Week 4) |
|
| Dexamethasone | Active Comparator | Dexamethasone 0.1% ophthalmic solution, maximum drop frequency administered for 2 weeks, followed by a tapering for 2 weeks (Weeks 3 and 4) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| LME636 60 mg/mL ophthalmic solution | Drug |
| ||
| Dexamethasone 0.1% ophthalmic solution |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Responders at Day 15 | Response was defined as a two-step decrease or more from baseline in Anterior Chamber (AC) Cell Grade as per Standardization of Uveitis Nomenclature (SUN). Baseline was defined as the measurement taken before drug administration on Day 1. Subjects receiving rescue treatment on or before Day 15 were considered non-responders. Only one eye contributed to the analysis. | Baseline (Day 1), Day 15 |
| Mean Best Corrected Visual Acuity (BCVA) at Each Visit | Visual Acuity (VA) with the subject's best spectacles or other visual corrective devices was measured using an Early Treatment of Diabetic Retinopathy Study (ETDRS) or Snellen visual acuity chart and reported in letters read correctly. An increase (gain) in letters read indicates improvement. Only one eye contributed to the analysis. | Baseline (Day 1), Day 4, Day 8, Day 15, Day 22, Day 29 |
| Mean Intraocular Pressure (IOP) at Each Visit | IOP (fluid pressure inside the eye) was assessed using Goldmann applanation tonometry or Tonopen and reported in millimeters mercury (mmHg). A higher IOP can be a greater risk factor for developing glaucoma or glaucoma progression (leading to optic nerve damage). Only one eye contributed to the analysis. | Baseline (Day 1), Day 4, Day 8, Day 15, Day 22, Day 29 |
| Number of Subjects With Increase From Baseline in Slit Lamp Parameters at Any Post-Treatment Visit | Slit-lamp biomicroscopy (examination) was performed to evaluate the anterior segment of the eye, including lids/lashes, conjunctiva, cornea, anterior chamber (cells and flare), iris, and lens. Ocular signs were categorized as Aqueous Flare, Aqueous Inflammatory Cell Grade, Keratic Precipitates, Lens, Limbal Injection, Status of Lens, Peripheral Anterior Synechia, and Posterior Synechia. An increase indicates worsening. Only one eye contributed to the analysis. | Baseline (Day 1), Day 4, Day 8, Day 15, Day 22, Day 29 |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Subjects With IOP Change From Baseline to Last On-Treatment Assessment | IOP was assessed using Goldmann applanation tonometry or Tonopen and reported in mmHg. A higher IOP can be a greater risk factor for developing glaucoma or glaucoma progression (leading to optic nerve damage). Only one eye contributed to the analysis. | Baseline (Day 1), Up to Day 29 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Clinical Scientist NIBR, Alcon | Alcon Research | Study Director |
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Of the 45 enrolled, 2 subjects were exited as screen failures prior to randomization and 4 subjects were randomized, but not treated. This reporting group includes all randomized subjects, as treated. Note: One subject randomized to LME636 was treated with dexamethasone instead.
Subjects were recruited from 10 study centers located in the United States.
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| ID | Title | Description |
|---|---|---|
| FG000 | LME636 | LME636 60 mg/mL ophthalmic solution, maximum drop frequency administered for 2 weeks, followed by a tapering for 1 week (Week 3) and 1 week of masked Vehicle administration (Week 4) |
| FG001 | Dexamethasone | Dexamethasone 0.1% ophthalmic solution, maximum drop frequency administered for 2 weeks, followed by a tapering for 2 weeks (Weeks 3 and 4) |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
This analysis population includes all randomized and treated subjects, as treated.
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| ID | Title | Description |
|---|---|---|
| BG000 | LME636 | LME636 60 mg/mL ophthalmic solution, maximum drop frequency administered for 2 weeks, followed by a tapering for 1 week (Week 3) and 1 week of masked Vehicle administration (Week 4) |
| BG001 | Dexamethasone |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| 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 | Number of Responders at Day 15 | Response was defined as a two-step decrease or more from baseline in Anterior Chamber (AC) Cell Grade as per Standardization of Uveitis Nomenclature (SUN). Baseline was defined as the measurement taken before drug administration on Day 1. Subjects receiving rescue treatment on or before Day 15 were considered non-responders. Only one eye contributed to the analysis. | This analysis population includes all subjects who received any study drug, had at least 1 post-baseline efficacy assessment, had no critical protocol deviations, and had a valid determination of response status for the primary endpoint (Per Protocol Analysis Set). | Posted | Count of Participants | Participants | No | Baseline (Day 1), Day 15 |
|
Adverse events (AEs) were collected from time of consent for the duration of a subject's participation in the study (up to 35 days). AEs are reported as pretreatment, treatment-emergent, and posttreatment.
An AE was defined as any untoward medical occurrence in a subject who is administered a study treatment regardless of whether or not the event has a causal relationship with the treatment. AEs were obtained through solicited and spontaneous comments from participants and through observations by the Investigator as outlined in the study protocol.
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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 | Pretreatment | All subjects who consented to participate in the study prior to initiation of study treatment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Multiple sclerosis | Nervous system disorders | MedDRA (17.0) | Systematic Assessment | Not related |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anterior chamber cell | Eye disorders | MedDRA (17.0) | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Ophthalmology & Medical Lead, Translational Medicine, NIBR | Alcon, A Novartis Division | 1-888-451-3937 | alcon.medinfo@alcon.com |
| ID | Term |
|---|---|
| D014606 | Uveitis, Anterior |
| ID | Term |
|---|---|
| D015864 | Panuveitis |
| D014605 | Uveitis |
| D014603 | Uveal Diseases |
| D005128 | Eye Diseases |
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| ID | Term |
|---|---|
| D009883 | Ophthalmic Solutions |
| D003907 | Dexamethasone |
| ID | Term |
|---|---|
| D019999 | Pharmaceutical Solutions |
| D012996 | Solutions |
| D004364 | Pharmaceutical Preparations |
| D045506 | Therapeutic Uses |
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| Drug |
|
| LME636 Vehicle | Drug | Inactive ingredients used for masking purposes |
|
| Number of Subjects With an Increase From Baseline in Dilated Fundus Parameters at Any Post-Treatment Visit | The dilated fundus examination was performed to evaluate the health of the vitreous, optic disc, retinal vessels, macula, and retinal periphery. An increase indicates worsening. Only one eye contributed to the analysis. | Baseline (Day 1), Day 4, Day 8, Day 15, Day 22, Day 29 |
| Mean Change From Baseline in BCVA at Each Visit | Visual Acuity (VA) was measured with the participant's best spectacles or other visual corrective device in place using an ETDRS or Snellen visual acuity chart. Improvement of BCVA was defined as an increase (gain) in letters read from the baseline assessment. Only one eye contributed to the analysis. | Baseline (Day 1), Day 4, Day 8, Day 15, Day 22, Day 29 |
| Time-to-Response | Time-to-Response was defined as the number of days from baseline to the first scheduled visit when a two-step decrease or more from baseline in AC Cell Grade (as per SUN) was observed. Time-to-Response is reported as number of subjects presenting time-to-response by visit. Only one eye contributed to the analysis. | Baseline (Day 1), Up to Day 15 |
| Use of Rescue Treatment | Use of rescue treatment is presented as the number of subjects with first use of rescue treatment by visit. Subjects receiving rescue medication were not considered withdrawn and the collection of data continued after discontinuation of study treatment. Only one eye contributed to the analysis. | Day 4, Day 8, Day 15 |
| Mean Serum Concentration of Total LME636 at Each Visit | Serum concentrations at each collection time point were quantitated, where possible, using a validated immunoassay method. Concentrations below the limit of quantification (BLQ), defined as 0.25 ng/mL, were reported as NA with no imputation for missing data. | Baseline (Day 1), Day 4, Day 8, Day 15, Day 22, Day 29 |
| Number of Subjects With Anti-LME636 Antibodies Present at Each Visit | Serum samples were collected and assessed for anti-LME636 antibodies. Samples collected from subjects in the LME636 dose group were analyzed for anti-LME636 antibodies. For subjects in the dexamethasone group, only the samples collected on Day 1 (ie, prior to the start of treatment) were analyzed for anti-LME636 antibodies. | Day 1, Day 4, Day 8, Day 15, Day 22, Day 29 |
| Unable to draw blood-prior to treatment |
|
| Criteria not met-prior to treatment |
|
| Adverse Event |
|
| Withdrawal by Subject |
|
| Criteria not met |
|
Dexamethasone 0.1% ophthalmic solution, maximum drop frequency administered for 2 weeks, followed by a tapering for 2 weeks (Weeks 3 and 4)
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants | No |
|
| OG001 | Dexamethasone | Dexamethasone 0.1% ophthalmic solution, maximum drop frequency administered for 2 weeks, followed by a tapering for 2 weeks (Weeks 3 and 4) |
|
|
| Primary | Mean Best Corrected Visual Acuity (BCVA) at Each Visit | Visual Acuity (VA) with the subject's best spectacles or other visual corrective devices was measured using an Early Treatment of Diabetic Retinopathy Study (ETDRS) or Snellen visual acuity chart and reported in letters read correctly. An increase (gain) in letters read indicates improvement. Only one eye contributed to the analysis. | This analysis population includes all subjects who received any study drug (Safety Analysis Set). Number Analyzed is the number of subjects with data at visit. | Posted | Mean | Standard Deviation | letters | Baseline (Day 1), Day 4, Day 8, Day 15, Day 22, Day 29 |
|
|
|
| Primary | Mean Intraocular Pressure (IOP) at Each Visit | IOP (fluid pressure inside the eye) was assessed using Goldmann applanation tonometry or Tonopen and reported in millimeters mercury (mmHg). A higher IOP can be a greater risk factor for developing glaucoma or glaucoma progression (leading to optic nerve damage). Only one eye contributed to the analysis. | Safety Analysis Set. Number Analyzed is the number of subjects with data at visit. | Posted | Mean | Standard Deviation | mmHg | Baseline (Day 1), Day 4, Day 8, Day 15, Day 22, Day 29 |
|
|
|
| Primary | Number of Subjects With Increase From Baseline in Slit Lamp Parameters at Any Post-Treatment Visit | Slit-lamp biomicroscopy (examination) was performed to evaluate the anterior segment of the eye, including lids/lashes, conjunctiva, cornea, anterior chamber (cells and flare), iris, and lens. Ocular signs were categorized as Aqueous Flare, Aqueous Inflammatory Cell Grade, Keratic Precipitates, Lens, Limbal Injection, Status of Lens, Peripheral Anterior Synechia, and Posterior Synechia. An increase indicates worsening. Only one eye contributed to the analysis. | Safety Analysis Set | Posted | Number | participants | Baseline (Day 1), Day 4, Day 8, Day 15, Day 22, Day 29 |
|
|
|
| Primary | Number of Subjects With an Increase From Baseline in Dilated Fundus Parameters at Any Post-Treatment Visit | The dilated fundus examination was performed to evaluate the health of the vitreous, optic disc, retinal vessels, macula, and retinal periphery. An increase indicates worsening. Only one eye contributed to the analysis. | Safety Analysis Set | Posted | Number | participants | Baseline (Day 1), Day 4, Day 8, Day 15, Day 22, Day 29 |
|
|
|
| Secondary | Number of Subjects With IOP Change From Baseline to Last On-Treatment Assessment | IOP was assessed using Goldmann applanation tonometry or Tonopen and reported in mmHg. A higher IOP can be a greater risk factor for developing glaucoma or glaucoma progression (leading to optic nerve damage). Only one eye contributed to the analysis. | Safety Analysis Set | Posted | Count of Participants | Participants | No | Baseline (Day 1), Up to Day 29 |
|
|
|
| Secondary | Mean Change From Baseline in BCVA at Each Visit | Visual Acuity (VA) was measured with the participant's best spectacles or other visual corrective device in place using an ETDRS or Snellen visual acuity chart. Improvement of BCVA was defined as an increase (gain) in letters read from the baseline assessment. Only one eye contributed to the analysis. | Safety Analysis Set. Number Analyzed is the number of subjects with data at visit. | Posted | Mean | Standard Deviation | letters | Baseline (Day 1), Day 4, Day 8, Day 15, Day 22, Day 29 |
|
|
|
| Secondary | Time-to-Response | Time-to-Response was defined as the number of days from baseline to the first scheduled visit when a two-step decrease or more from baseline in AC Cell Grade (as per SUN) was observed. Time-to-Response is reported as number of subjects presenting time-to-response by visit. Only one eye contributed to the analysis. | Per Protocol Analysis Set | Posted | Count of Participants | Participants | No | Baseline (Day 1), Up to Day 15 |
|
|
|
| Secondary | Use of Rescue Treatment | Use of rescue treatment is presented as the number of subjects with first use of rescue treatment by visit. Subjects receiving rescue medication were not considered withdrawn and the collection of data continued after discontinuation of study treatment. Only one eye contributed to the analysis. | Per Protocol Analysis Set | Posted | Count of Participants | Participants | No | Day 4, Day 8, Day 15 |
|
|
|
| Secondary | Mean Serum Concentration of Total LME636 at Each Visit | Serum concentrations at each collection time point were quantitated, where possible, using a validated immunoassay method. Concentrations below the limit of quantification (BLQ), defined as 0.25 ng/mL, were reported as NA with no imputation for missing data. | This analysis population includes all subjects who received investigative product (IP) and had at least 1 evaluable serum sample following IP exposure.(Pharmacokinetics Analysis Set). Number Analyzed is the number of subjects with data at visit. | Posted | Mean | Standard Deviation | ng/mL | Baseline (Day 1), Day 4, Day 8, Day 15, Day 22, Day 29 |
|
|
|
| Secondary | Number of Subjects With Anti-LME636 Antibodies Present at Each Visit | Serum samples were collected and assessed for anti-LME636 antibodies. Samples collected from subjects in the LME636 dose group were analyzed for anti-LME636 antibodies. For subjects in the dexamethasone group, only the samples collected on Day 1 (ie, prior to the start of treatment) were analyzed for anti-LME636 antibodies. | This analysis population includes all subjects with available immunogenicity data and no protocol deviations with relevant impact on the data (Immunogenicity Set). | Posted | Count of Participants | Participants | No | Day 1, Day 4, Day 8, Day 15, Day 22, Day 29 |
|
|
|
| 0 |
| 45 |
| 0 |
| 45 |
| 0 |
| 45 |
| EG001 | LME636 | All subjects exposed to LME636 ophthalmic solution | 0 | 29 | 1 | 29 | 13 | 29 |
| EG002 | Dexamethasone | All subjects exposed to Dexamethasone ophthalmic solution | 0 | 10 | 0 | 10 | 6 | 10 |
| EG003 | Posttreatment | All subjects from the conclusion of treatment until exit from the study | 0 | 39 | 0 | 39 | 0 | 39 |
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| Anterior chamber flare | Eye disorders | MedDRA (17.0) | Systematic Assessment |
|
| Ciliary muscle spasm | Eye disorders | MedDRA (17.0) | Systematic Assessment |
|
| Eye irritation | Eye disorders | MedDRA (17.0) | Systematic Assessment |
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| Eye pain | Eye disorders | MedDRA (17.0) | Systematic Assessment |
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| Iridocyclitis | Eye disorders | MedDRA (17.0) | Systematic Assessment |
|
| Iris adhesions | Eye disorders | MedDRA (17.0) | Systematic Assessment |
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| Iritis | Eye disorders | MedDRA (17.0) | Systematic Assessment |
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| Lacrimation increased | Eye disorders | MedDRA (17.0) | Systematic Assessment |
|
| Photophobia | Eye disorders | MedDRA (17.0) | Systematic Assessment |
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| Vitreous detachment | Eye disorders | MedDRA (17.0) | Systematic Assessment |
|
| Intraocular pressure increased | Investigations | MedDRA (17.0) | Systematic Assessment |
|
| Dysgeusia | Nervous system disorders | MedDRA (17.0) | Systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA (17.0) | Systematic Assessment |
|
Sponsor reserves the right of prior review of any publication or presentation of information related to the study.
| D020228 |
| Pharmacologic Actions |
| D020164 | Chemical Actions and Uses |
| D020313 | Specialty Uses of Chemicals |
| D011246 | Pregnadienetriols |
| D011245 | Pregnadienes |
| D011278 | Pregnanes |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| D013259 | Steroids, Fluorinated |
| Day 4 |
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| Day 8 |
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| Day 15 |
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| Day 22 |
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| Day 29 |
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| Day 4 |
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| Day 8 |
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| Day 15 |
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| Day 22 |
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| Day 29 |
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| Keratic Precipitates |
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| Lens |
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| Limbal Injection |
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| Status of Lens |
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| Peripheral Anterior Synechia |
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| Posterior Synechiae |
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| Retina |
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| Vitreous |
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| Increase 6-10 mmHg |
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| -5 mmHg Decrease - 5 mmHg Increase |
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| Decrease 6-10 mmHg |
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| Decrease 11-30 mmHg |
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| Decrease > 30 mmHg |
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| Change from BL at Day 4 |
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| Change from BL at Day 8 |
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| Change from BL at Day 15 |
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| Change from BL at Day 22 |
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| Change from BL at Day 29 |
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| Day 15 |
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| Non-Responder |
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| No Rescue |
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| Day 15 |
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| Day 22 |
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| Day 29 |
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