First-in-Human Study of LHA510 in Elderly Subjects and Patients With Age-Related Macular Degeneration

Study Overview
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Brief Summary
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The purpose of this first-in-human study is to assess the local ocular and systemic safety and tolerability of LHA510 eye drops when administered at various concentrations and dosing frequencies.

Detailed Description
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This first-in-human study was conducted in two parts. Part 1 was a single ascending dose (SAD) design to assess the local ocular and systemic safety and tolerability of a single topical eye drop of LHA510 administered at various concentrations. Four separate cohorts of unique elderly subjects (55 to 80 years) were utilized, with each cohort randomized to receive either topical LHA510 or vehicle in a 3:1 ratio as a single dose. A disposition evaluation was performed 7 days later. Part 2 was a multiple ascending dose (MAD) design to assess the local ocular and systemic safety and tolerability of LHA510 administered at various concentrations and dosing frequencies. Six separate cohorts of unique AMD subjects were utilized, with each cohort randomized to receive either topical LHA510 or vehicle in a 3:1 ratio for 7 days. A disposition evaluation was performed 14 days after the first dose of study drug. A review of all available safety data was conducted by the Sponsor and the PI(s) prior to dose escalation (cohort progression). The same concentrations levels were used in Part 1 and Part 2 and are ordered as Lowest, Next Lowest, Next Highest, and Highest.

Official Title
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A Randomized, Double-Masked, Vehicle-Controlled, First-in-Human Study to Assess the Safety, Tolerability, and Pharmacokinetics of Single and Multiple Ascending Doses of Topically Delivered LHA510 in Elderly Subjects and Patients With Age-Related Macular Degeneration

Conditions
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Age-Related Macular Degeneration

Intervention / Treatment
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* Drug: LHA510 Ophthalmic Suspension
* Drug: LHA510 Vehicle


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provide written informed consent. Vital signs within the following ranges: oral body temperature between 35.0-37.5 °C systolic blood pressure, 90-150 mm Hg diastolic blood pressure, 50-90 mm Hg pulse rate, 40 - 100 bpm. Weigh at least 50 kg. Able to communicate well with the investigator. Able to understand and comply with the requirements of the study. Additional eligibility criteria for Part 2 (AMD subjects): Evidence of AMD in one or both eyes. Age 55-90. Other protocol-defined inclusion criteria may apply. Exclusion Criteria: Any currently active ocular condition that requires use of topical eye drops. Use of contact lens over the course of the study. Abnormal corneal examination results at screening or eligibility. History of any ocular surgery within the past 6 months prior to study participation. Use of other investigational drugs within 30 days of enrollment. History of hypersensitivity or allergy to any of the study drugs (including fluorescein) or to drugs of similar chemical classes. History of clinically significant ECG abnormalities, or any ECG abnormality at screening or eligibility. Known history or current clinically significant arrhythmias. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years. Pregnant or nursing (lactating) women. Women of child-bearing potential. Use of any prohibited medication as specified in the protocol. Donation or loss of 400 ml or more of blood within eight (8) weeks prior to initial dosing. Low hemoglobin levels at screening or eligibility as specified in the protocol. Significant illness as specified in the protocol. History of drug or alcohol abuse within the 12 months prior to dosing. Additional exclusion criteria for Part 1 (healthy subjects): Abnormal thickness of the central retinal subfield on OCT at screening. History of any chronic eye disease other than refractive error, incipient cataract, strabismic amblyopia, or anisometropic amblyopia. Additional exclusion criteria for Part 2 (AMD subjects): Any of the following treatments to the study eye within 28 days prior to dosing: ranibizumab (Lucentis®), aflibercept (Eylea®), bevacizumab (Avastin®), pegaptanib (Macugen®), or any other VEGF inhibitor. Patients who have required and received regular monthly injections of these drugs in the months preceding the study.

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LHA510 Part 1<br>LHA510 Ophthalmic Suspension in 1 of 4 concentrations, 1 drop instilled in the study eye as a single dose during Part 1 | Drug: LHA510 Ophthalmic Suspension<br>* Ophthalmic suspension in 4 concentration levels topically administered in Part 1 and Part 2<br>|
| Placebo Comparator: LHA510 Vehicle Part 1<br>Inactive ingredients, 1 drop instilled in the study eye as a single dose during Part 1 | Drug: LHA510 Vehicle<br>* Inactive ingredients used for masking purposes<br>|
| Experimental: LHA510 Part 2<br>LHA510 Ophthalmic Suspension in 1 of 4 concentrations, 1 drop instilled in the study eye once, twice, or three times daily for 7 days during Part 2 | Drug: LHA510 Ophthalmic Suspension<br>* Ophthalmic suspension in 4 concentration levels topically administered in Part 1 and Part 2<br>|
| Placebo Comparator: LHA510 Vehicle Part 2<br>Inactive ingredients, 1 drop instilled in the study eye once, twice, or 3 times daily for 7 days during Part 2 | Drug: LHA510 Vehicle<br>* Inactive ingredients used for masking purposes<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With a Serious Adverse Event That, in the Opinion of the Investigator, is Related to the Study Drug, Part 1 | A serious adverse event (SAE) was defined as any event which is fatal or life-threatening, which requires or prolongs hospitalization, which is significantly or permanently disabling or incapacitating, which constitutes a congenital anomaly or a birth defect, or which is medically significant, may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed above. | From time of consent until 30 days after stopping the trial/study drug | 
| Number of Subjects With a Serious Adverse Event That, in the Opinion of the Investigator, is Related to the Study Drug, Part 2 | A serious adverse event (SAE) was defined as any event which is fatal or life-threatening, which requires or prolongs hospitalization, which is significantly or permanently disabling or incapacitating, which constitutes a congenital anomaly or a birth defect, or which is medically significant, may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed above. | From time of consent until 30 days after stopping the trial/study drug | 
| Number of Subjects Experiencing a Non-serious Adverse Event, Part I | An adverse event (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. An AE, therefore, could be any unfavorable or unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the study treatment, whether or not related to the treatment. | From time of consent until 30 days after stopping the trial/study drug | 
| Number of Subjects Experiencing a Non-serious Adverse Event, Part 2 | An adverse event (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. An AE, therefore, could be any unfavorable or unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the study treatment, whether or not related to the treatment. | From time of consent until 30 days after stopping the trial/study drug | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Observed Maximum Plasma (or Serum or Blood) Concentration Following Drug Administration [Mass / Volume] (Cmax), Part 2 | Plasma concentrations were quantitated using a high performance liquid chromatography/tandem mass spectometry method.Timepoints of assessment for Arms 1-4 were Days 1 and 7: 0h (pre-dose), 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 12h and 24h post-dose; and Day 15: 0h. Timepoints of assessment for LHA Highest BID were Days 1 and 7: 0h (pre-dose), 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h and 12h post-dose; and Day 15: 0h. Timepoints of assessment for LHA510 Highest TID were Days 1 and 7: 0h (pre-dose), 0.25h, 0.5h, 1h, 2h, 4h, 0h (pre-2nd dose), 0.5h, 2h, 0h (pre-3rd dose), 0.25h, 0.5h, 1h, 2h, 4h, 12h post-dose; and Day 15: 0h. | Up to Day 15 | 
| The Time to Reach the Maximum Concentration After Drug Administration [Time] (Tmax), Part 2 | Plasma concentrations were quantitated using a high performance liquid chromatography/tandem mass spectometry method. Timepoints of assessment for Arms 1-4 were Days 1 and 7: 0h (pre-dose), 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 12h and 24h post-dose; and Day 15: 0h. Timepoints of assessment for LHA Highest BID were Days 1 and 7: 0h (pre-dose), 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h and 12h post-dose; and Day 15: 0h. Timepoints of assessment for LHA510 Highest TID were Days 1 and 7: 0h (pre-dose), 0.25h, 0.5h, 1h, 2h, 4h, 0h (pre-2nd dose), 0.5h, 2h, 0h (pre-3rd dose), 0.25h, 0.5h, 1h, 2h, 4h, 12h post-dose; and Day 15: 0h. | Up to Day 15 | 
| The Area Under the Plasma (or Serum or Blood) Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration [Mass x Time/Volume] (AUClast), Part 2 | Plasma concentrations were quantitated using a high performance liquid chromatography/tandem mass spectometry method. Timepoints of assessment for Arms 1-4 were Days 1 and 7: 0h (pre-dose), 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 12h and 24h post-dose; and Day 15: 0h. Timepoints of assessment for LHA Highest BID were Days 1 and 7: 0h (pre-dose), 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h and 12h post-dose; and Day 15: 0h. Timepoints of assessment for LHA510 Highest TID were Days 1 and 7: 0h (pre-dose), 0.25h, 0.5h, 1h, 2h, 4h, 0h (pre-2nd dose), 0.5h, 2h, 0h (pre-3rd dose), 0.25h, 0.5h, 1h, 2h, 4h, 12h post-dose; and Day 15: 0h. | Up to Day 15 | 
| The Terminal Elimination Half-life [Time] (T1/2), Part 2 | Plasma concentrations were quantitated using a high performance liquid chromatography/tandem mass spectometry method. Timepoints of assessment for Arms 1-4 were Days 1 and 7: 0h (pre-dose), 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 12h and 24h post-dose; and Day 15: 0h. Timepoints of assessment for LHA Highest BID were Days 1 and 7: 0h (pre-dose), 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h and 12h post-dose; and Day 15: 0h. Timepoints of assessment for LHA510 Highest TID were Days 1 and 7: 0h (pre-dose), 0.25h, 0.5h, 1h, 2h, 4h, 0h (pre-2nd dose), 0.5h, 2h, 0h (pre-3rd dose), 0.25h, 0.5h, 1h, 2h, 4h, 12h post-dose; and Day 15: 0h. | Up to Day 15 | 
| Change From Baseline in Diastolic Blood Pressure at Each Post Dose Timepoint, Part 1 | Diastolic blood pressure (pressure in the arteries when the heart rests between beats) was measured using an automated validated device, with an appropriately sized cuff, and assessed in the sitting position after the subject had rested for at least 3 minutes, and again (when required) after 3 minutes in the standing position. | Day 1: 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 12h and 24h post-dose | 
| Change From Baseline in Systolic Blood Pressure at Each Post Dose Timepoint, Part 1 | Systolic blood pressure (pressure when the heart is contracting) was measured using an automated validated device, with an appropriately sized cuff, and assessed in the sitting position after the subject had rested for at least 3 minutes, and again (when required) after 3 minutes in the standing position. | Day 1: 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 12h and 24h post-dose | 
| Change From Baseline in Mean Arterial Blood Pressure at Each Post Dose Timepoint, Part 1 | Mean arterial blood pressure (average pressure in the arteries during one cardiac cycle) was measured using an automated validated device, with an appropriately sized cuff, and assessed in the sitting position after the subject had rested for at least 3 minutes, and again (when required) after 3 minutes in the standing position. | Day 1: 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 12h and 24h post-dose | 
| Change From Baseline in Diastolic Blood Pressure at Each Post Dose Timepoint, Part 2 | Diastolic blood pressure (pressure in the arteries when the heart rests between beats) was measured using an automated validated device, with an appropriately sized cuff, and assessed in the sitting position after the subject had rested for at least 3 minutes, and again (when required) after 3 minutes in the standing position. | Day 1 and 7: 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 12h and 24h post-dose | 
| Change From Baseline in Systolic Blood Pressure at Each Post Dose Timepoint, Part 2 | Systolic blood pressure (pressure when the heart is contracting) was measured using an automated validated device, with an appropriately sized cuff, and assessed in the sitting position after the subject had rested for at least 3 minutes, and again (when required) after 3 minutes in the standing position. | Day 1 and 7: 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 12h and 24h post-dose | 
| Change From Mean Arterial Blood Pressure at Each Post Dose Timepoint, Part 2 | Mean arterial blood pressure (average pressure in the arteries during one cardiac cycle) was measured using an automated validated device, with an appropriately sized cuff, and assessed in the sitting position after the subject had rested for at least 3 minutes, and again (when required) after 3 minutes in the standing position. | Day 1 and 7: 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 12h and 24h post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AMD, LHA510, First in human, Safety, Tolerability, Pharmacokinetics, Elderly, Age-Related Macular Degeneration, Ocular, Eye drop