A Study to Evaluate Safety and Efficacy of rhNGF Eye Solution vs Vehicle in Patients With Moderate to Severe Dry Eye

Sponsor
Dompé Farmaceutici S.p.A (Industry)
Overall Status
Completed
CT.gov ID
NCT03982368
Collaborator
(none)
261
12
3
13.2
21.8
1.7

Study Details

Study Description

Brief Summary

The objective of this study is to assess the efficacy and safety of rhNGF eye drops at 20 μg/ml concentration administered two or three times daily for 4 weeks in patients with moderate to severe dry eye.

Condition or Disease Intervention/Treatment Phase
  • Drug: rhNGF 20 μg/ml
  • Drug: rhNGF 20 μg/ml + vehicle
  • Other: Vehicle
Phase 2

Detailed Description

This is a 4 weeks, Phase II, multicenter, randomized, double-masked, vehicle-controlled, parallel group study with 12 weeks of follow-up, designed to perform dose-ranging and to evaluate safety and efficacy of recombinant human Nerve Growth Factor (rhNGF) eye drops solution versus vehicle, in patients with moderate to severe dry eye (DE).

Test product is rhNGF 20 μg/ml; reference product is vehicle. Test and reference will be instilled in both eyes according to the following scheme:

Group 1: one drop of rhNGF 20 μg/ml is instilled in both eyes three times daily (every 6-8 hours, e.g. 7:00 am, 02:00 pm; 09:00 pm).

Group 2: one drop of rhNGF 20 μg/ml is instilled in both eyes two times daily (in the morning and in the evening) plus one drop (40 μL) of vehicle (placebo) is instilled in both eyes once daily in the afternoon.

Group 3: one drop (40 μL) of vehicle (placebo) is instilled in both eyes three times daily (every 6-8 hours, e.g. 7:00 am, 02:00 pm; 09:00 pm).

Approximate randomization 1:1:1 of 261 patients to rhNGF eye drops solution 20 μg/ml TID (87 patients) or rhNGF eye drops solution 20 μg/ml BID + vehicle eye drop SID (86 patients) or vehicle eye drops solution (88 patients) TID for 4 weeks was applied.

Study Design

Study Type:
Interventional
Actual Enrollment :
261 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Intervention Model Description:
Parallel groupsParallel groups
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:
Double masked
Primary Purpose:
Treatment
Official Title:
A 4 Weeks, Phase II, Multicenter, Randomized, Double-masked, Vehicle-controlled, Parallel Group Study With 12 Weeks of Follow-up to Evaluate Safety and Efficacy of rhNGF Eye Drops Solution vs Vehicle in Moderate to Severe Dry Eye.
Actual Study Start Date :
Jun 10, 2019
Actual Primary Completion Date :
Jul 15, 2020
Actual Study Completion Date :
Jul 15, 2020

Arms and Interventions

Arm Intervention/Treatment
Experimental: rhNGF 20 μg/ml TID

One drop of rhNGF 20 μg/ml will be instilled in both eyes three times daily (every 6-8 hours)

Drug: rhNGF 20 μg/ml
one drop of rhNGF 20 μg/ml will be instilled in both eyes three times daily (every 6-8 hours)
Other Names:
  • cenegermin
  • Experimental: rhNGF 20 μg/ml BID + vehicle OD

    One drop of rhNGF 20 μg/ml will be instilled in both eyes two times daily (BID) plus one drop (40 μL) of vehicle will be instilled in both eyes once daily (OD) (every 6-8 hours)

    Drug: rhNGF 20 μg/ml + vehicle
    one drop of rhNGF 20 μg/ml will be instilled in both eyes two times daily plus one drop (40 μL) of vehicle will be instilled in both eyes once daily (every 6-8 hours). rhNGF will be instilled in the morning and in the evening while the vehicle will be instilled in the afternoon.
    Other Names:
  • cenegermin + placebo
  • Placebo Comparator: Vehicle TID

    Vehicle eye one drop will be instilled in both eyes three times daily (every 6-8 hours)

    Other: Vehicle
    one drop of vehicle will be instilled in both eyes three times daily (every 6-8 hours)
    Other Names:
  • placebo
  • Outcome Measures

    Primary Outcome Measures

    1. Change From Baseline in Schirmer I Test (Without Anesthesia) vs Week 4 - Full Analysis Set [Baseline, week 4]

      The Schirmer test is used in ophthalmic examination to measure tear production for the diagnosis of conditions such as keratoconjunctivitis sicca and dry eye. Without previously instilling anesthetic drops, the Schirmer strip is inserted into the lower conjunctival sac at the junction of the lateral and middle thirds, avoiding touching the cornea, and the length of wetting strips in millimeters is recorded after 5 minutes. The patients will be instructed to close their eyes gently. After 5 minutes have elapsed, the Schirmer test strip will be removed and the length of the tear absorption on the strip will be measured (millimeters/5 minutes) Cutoff values: <5 mm - pathologic dry eye 5-10 mm - marginal dry eye >10 and <30 mm - normal secretion

    2. Change From Baseline in Schirmer I Test (Without Anesthesia) vs Week 4 - Per Protocol Set [Baseline, week 4]

      The Schirmer test is used in ophthalmic examination to measure tear production for the diagnosis of conditions such as keratoconjunctivitis sicca and dry eye. Without previously instilling anesthetic drops, the Schirmer strip is inserted into the lower conjunctival sac at the junction of the lateral and middle thirds, avoiding touching the cornea, and the length of wetting strips in millimeters is recorded after 5 minutes. The patients will be instructed to close their eyes gently. After 5 minutes have elapsed, the Schirmer test strip will be removed and the length of the tear absorption on the strip will be measured (millimeters/5 minutes) Cutoff values: <5 mm - pathologic dry eye 5-10 mm - marginal dry eye >10 and <30 mm - normal secretion

    Secondary Outcome Measures

    1. Change From Baseline in Symptoms Questionnaire (SANDE) Scores for Severity vs Week 4 - Full Analysis Set [Baseline, week 4]

      The SANDE (symptom assessment in dry eye) score is composed by two questions presented in visual analog scale. The two questions assess the frequency and severity of dry eye syndrome. The global score is calculated by taking the square root of the product of the severity of symptoms per the frequency of symptoms. The SANDE scale ranges from 0 to 100 with 100 being the maximal amount of dry eye symptoms and 0 being the minimal amount of dry eye symptoms.

    2. Change From Baseline in Symptoms Questionnaire (SANDE) Scores for Severity vs Week 4 - Per Protocol Set [Baseline, week 4]

      The SANDE (symptom assessment in dry eye) score is composed by two questions presented in visual analog scale. The two questions assess the frequency and severity of dry eye syndrome. The global score is calculated by taking the square root of the product of the severity of symptoms per the frequency of symptoms. The SANDE scale ranges from 0 to 100 with 100 being the maximal amount of dry eye symptoms and 0 being the minimal amount of dry eye symptoms.

    3. Change From Baseline in Symptoms Questionnaire (SANDE) Scores for Frequency vs Week 4 - Full Analysis Set [Baseline, week 4]

      The SANDE (symptom assessment in dry eye) score is composed by two questions presented in visual analog scale. The two questions assess the frequency and severity of dry eye syndrome.The SANDE global score is calculated by taking the square root of the product of the frequency of symptoms and the severity of symptoms. The SANDE scale ranges from 0 to 100 wi.100 being the maximal amount of dry eye symptoms and 0 being the minimal amount of dry eye symptoms

    4. Change From Baseline in Symptoms Questionnaire (SANDE) Scores for Frequency vs Week 4 - Per Protocol Set [Baseline, week 4]

      The SANDE (symptom assessment in dry eye) score is composed by two questions presented in visual analog scale. The two questions assess the frequency and severity of dry eye syndrome. The SANDE score is calculated by taking the square root of the product of the frequency of symptoms score. The SANDE scale ranges from 0 to 100 wi.100 being the maximal amount of dry eye symptoms and 0 being the minimal amount of dry eye symptoms.

    5. Change From Baseline in Schirmer II Test (With Anesthesia) vs Week 4 - Full Analysis Set [Baseline, week 4]

      The Schirmer II test is performed as the Schirmer I test after instilling anesthetic drops. The Schirmer strips are inserted into the lower conjunctival sac at the junction of the lateral and middle thirds, avoiding touching the cornea, and the length of wetting strips in millimeters is recorded after 5 minutes. All patients are seated at rest with their eyes closed, and the lower cul-de-sac is gently dried with a cotton applicator before the placement of strips. Cut-off values: <5 mm - pathologic dry eye 5-10 mm - marginal dry eye >10 and <30 mm - normal secretion

    6. Change From Baseline in Schirmer II Test (With Anesthesia) vs Week 4 - Per Protocol Set [Baseline, week 4]

      The Schirmer II test is performed as the Schirmer I test after instilling anesthetic drops. The Schirmer strips are inserted into the lower conjunctival sac at the junction of the lateral and middle thirds, avoiding touching the cornea, and the length of wetting strips in millimeters is recorded after 5 minutes. All patients are seated at rest with their eyes closed, and the lower cul-de-sac is gently dried with a cotton applicator before the placement of strips. Cut-off values: <5 mm - pathologic dry eye 5-10 mm - marginal dry eye >10 and <30 mm - normal secretion

    7. Change From Baseline in Corneal and Conjunctiva Vital Staining With Fluorescein (National Eye Institute [NEI] Scales) vs Week 4 - Full Analysis Set [Baseline, week 4]

      Corneal staining total score is defined as the sum of scores from 5 corneal areas: Central, Superior, Temporal, Nasal, and Inferior. The score for each area ranges from 0 to 3 where grade 0 reflects normal/healthy situation, whereas grade 3 reflects a severe damage. Thus, the corneal staining total score can range from 0 to 15 where the higher the score the worse is the outcome. The conjunctiva is divided into a superior paralimbal area, an inferior paralimbal area and a peripheral area with a grading scale of 0-3 where grade 0 reflects normal/healthy situation, whereas grade 3 reflects a severe damage and with a maximal score of 9 for the nasal and temporal conjunctiva. Thus, the conjunctival staining total score can range from 0 to 18 where the higher the score the worse is the outcome. Corneal and conjunctiva vital staining total score is the sum of corneal staining total score and conjunctiva total score.

    8. Change From Baseline in Corneal and Conjunctiva Vital Staining With Fluorescein (National Eye Institute [NEI] Scales) vs Week 4 - Per Protocol Set [Baseline, week 4]

      Corneal staining total score is defined as the sum of scores from 5 corneal areas: Central, Superior, Temporal, Nasal, and Inferior. The score for each area ranges from 0 to 3 where grade 0 reflects normal/healthy situation, whereas grade 3 reflects a severe damage. Thus, the corneal staining total score can range from 0 to 15 where the higher the score the worse is the outcome. The conjunctiva is divided into a superior paralimbal area, an inferior paralimbal area and a peripheral area with a grading scale of 0-3 where grade 0 reflects normal/healthy situation, whereas grade 3 reflects a severe damage and with a maximal score of 9 for the nasal and temporal conjunctiva. Thus, the conjunctival staining total score can range from 0 to 18 where the higher the score the worse is the outcome. Corneal and conjunctiva vital staining total score is the sum of corneal staining total score and conjunctiva total score.

    9. Change From Baseline in Tear Film Break-Up Time (TFBUT) vs Week 4 - Full Analysis Set [Baseline, week 4]

      Tear film break-up time (TFBUT) is the time taken to appear first dry spot on cornea after a complete blinking. TFBUT measurement is an easy and fast method used to assess the stability of tear film. It is a standard diagnostic procedure in the dry eye clinics. TFBUT is measured by determining the time to tear break-up. The TFBUT is performed after instillation of 5 μL of 2% preservative-free sodium fluorescein solution into the inferior conjunctival cul-de-sac of each eye. The patient is instructed to blink several times to thoroughly mix the fluorescein with the tear film. A TFBUT greater than 15 seconds is considered normal, while a break time of less than 10 seconds is to be considered pathological.

    10. Change From Baseline in Tear Film Break-Up Time (TFBUT) vs Week 4 - Per Protocol Set [Baseline, week 4]

      Tear film break-up time (TFBUT) is the time taken to appear first dry spot on cornea after a complete blinking. TFBUT measurement is an easy and fast method used to assess the stability of tear film. It is a standard diagnostic procedure in the dry eye clinics. TFBUT is measured by determining the time to tear break-up. The TFBUT is performed after instillation of 5 μL of 2% preservative-free sodium fluorescein solution into the inferior conjunctival cul-de-sac of each eye. The patient is instructed to blink several times to thoroughly mix the fluorescein with the tear film. A TFBUT greater than 15 seconds is considered normal, while a break time of less than 10 seconds is to be considered pathological.

    11. Number of Patients Who Experienced a Worsening in Symptom Scores (SANDE) and/or NEI Score ≥ 50% Assessed at Week 4 - Full Analysis Set [At week 4]

      The SANDE score is calculated by taking the square root of the product of the severity of symptoms score. The SANDE scale ranges from 0 to 100 with 100 being the maximal amount of dry eye symptoms and 0 being the minimal amount of dry eye symptoms. The NEI/Industry Workshop guidelines are used for grading the scale of corneal and conjunctival damage. The cornea is divided into five sectors (central, superior, inferior, nasal and temporal), each of which is scored on a scale of 0-3, with a maximal total corneal staining score of 15. Both nasally and temporally, the conjunctiva is divided into a superior paralimbal area, an inferior paralimbal area, and a peripheral area with a grading scale of 0-3 and with a maximal total score of 9 for the nasal and temporal conjunctiva (overall the total score ranged from 0-18). Briefly, grade 0 reflects normal/healthy situation, whereas grade 3 reflects a severe damage in the considered sector.

    12. Number of Patients Who Experienced a Worsening in Symptom Scores (SANDE) and/or NEI Score ≥ 50% Assessed at Week 4 - Per Protocol Set [At week 4]

      The SANDE score is calculated by taking the square root of the product of the severity of symptoms score. The SANDE scale ranges from 0 to 100 with 100 being the maximal amount of dry eye symptoms and 0 being the minimal amount of dry eye symptoms. The NEI/Industry Workshop guidelines are used for grading the scale of corneal and conjunctival damage. The cornea is divided into five sectors (central, superior, inferior, nasal and temporal), each of which is scored on a scale of 0-3, with a maximal total corneal staining score of 15. Both nasally and temporally, the conjunctiva is divided into a superior paralimbal area, an inferior paralimbal area, and a peripheral area with a grading scale of 0-3 and with a maximal total score of 9 for the nasal and temporal conjunctiva (overall the total score ranged from 0-18). Briefly, grade 0 reflects normal/healthy situation, whereas grade 3 reflects a severe damage in the considered sector.

    13. Change From Baseline in Quality of Life (Impact of Dry Eye on Everyday Life (IDEEL) Questionnaire vs Different Timepoints - Full Analysis Set [At weeks 4, 8, 12 and 16]

      IDEEL assesses quality of life, symptoms and treatment effects on patients with dry eye. The IDEEL contains 3 modules (Daily Activities, Treatment Satisfaction, and Symptom Bother) with a total of 57 questions. The Daily Activities Module is the quality of life instrument. It is comprised of 27 items. The IDEEL Treatment Satisfaction and Bother Module is divided into 2 sections, Treatment - In General and Treatment - Eye Drops. The Symptom Bother Module consists of 20 items in a single content domain, Symptom Bother. Scores for each dimensions ranged from 0 to 100. Higher scores for: dimension of the Dry Eye Impact on Daily Life module indicates less impact on daily activities; symptom-bother dimension indicates greater bother due to symptoms; satisfaction with Treatment Effectiveness dimension indicates greater satisfaction with treatment effectiveness; treatment-related bother/inconvenience indicates less treatment-related bother or inconvenience.

    14. Change From Baseline in Quality of Life (Impact of Dry Eye on Everyday Life (IDEEL) Questionnaire vs Different Timepoints - Per Protocol Set [At weeks 4, 8, 12 and 16]

      IDEEL assesses quality of life, symptoms and treatment effects on patients with dry eye. The IDEEL contains 3 modules (Daily Activities, Treatment Satisfaction, and Symptom Bother) with a total of 57 questions. The Daily Activities Module is the quality of life instrument. It is comprised of 27 items. The IDEEL Treatment Satisfaction and Bother Module is divided into 2 sections, Treatment - In General and Treatment - Eye Drops. The Symptom Bother Module consists of 20 items in a single content domain, Symptom Bother. Scores for each dimensions ranged from 0 to 100. Higher scores for: dimension of the Dry Eye Impact on Daily Life module indicates less impact on daily activities; symptom-bother dimension indicates greater bother due to symptoms; satisfaction with Treatment Effectiveness dimension indicates greater satisfaction with treatment effectiveness; treatment-related bother/inconvenience indicates less treatment-related bother or inconvenience.

    15. Patient Global Impression of Change (PGIC) - Full Analysis Set [At baseline and weeks 4, 8, 12 and 16]

      PGIC is a commonly used method of assessing clinically important change. With PGIC the qualitative assessment of meaningful change is determined by the patient on 7-items using a 0 (very much improved) to 10 (very much worse) scale.

    16. Patient Global Impression of Change (PGIC) - Per Protocol Set [At weeks 4, 8, 12 and 16]

      PGIC is a commonly used method of assessing clinically important change. With PGIC the qualitative assessment of meaningful change is determined by the patient on 7-items using a 0 (very much improved) to 10 (very much worse) scale.

    17. Change From Baseline in EQ-5D-3L Questionnaire to Different Timepoints - Full Analysis Set [At weeks 4, 8, 12 and 16]

      EQ-5D is a standardised measure of health status. - The EQ-5D 3 level version (EQ-5D-3L) consists of the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS) which are summed up. The EQ-5D-3L descriptive system comprises 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. This scale ranges from 5 (best case) to 15 (worst case). Each dimension has 3 levels: no problems, some problems, extreme problems (labelled 1-3). The respondent must indicate his/her health state by ticking (or placing a cross) in the box against the most appropriate statement in each of the 5 dimensions. - The EQ VAS records the respondent's self-rated health on a vertical, visual analogue scale where the endpoints are labelled 'Best imaginable health state' and 'Worst imaginable health state'. This is a quantitative measure of health outcome, judged by each respondent. Both for total and partial scores, the higher the score, the worse is the outcome.

    18. Change From Baseline in EQ-5D-3L Questionnaire to Different Timepoints - Per Protocol Set [Aat baseline and weeks 4, 8, 12 and 16]

      EQ-5D is a standardised measure of health status. - The EQ-5D 3 level version (EQ-5D-3L) consists of the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS) which are summed up. The EQ-5D-3L descriptive system comprises 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. This scale ranges from 5 (best case) to 15 (worst case). Each dimension has 3 levels: no problems, some problems, extreme problems (labelled 1-3). The respondent must indicate his/her health state by ticking (or placing a cross) in the box against the most appropriate statement in each of the 5 dimensions. - The EQ VAS records the respondent's self-rated health on a vertical, visual analogue scale where the endpoints are labelled 'Best imaginable health state' and 'Worst imaginable health state'. This is a quantitative measure of health outcome, judged by each respondent. Both for total and partial scores, the higher the score, the worse is the outcome.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 85 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    1. Male or female aged ≥ 18 years

    2. Patients with moderate to severe dry eye characterized by the following clinical features:

    3. Corneal and/or conjunctival staining with fluorescein using National Eye Institute (NEI) grading system > 3

    4. SANDE questionnaire >25 mm

    5. Schirmer test I (without anaesthesia) >2mm <10 mm/5 minutes

    6. Tear film break-up time (TFBUT) < 10 seconds in the worse eye

    7. The same eye (eligible eye) must fulfill all the above criteria

    8. Patients diagnosed with dry eye at least 6 months before enrolment (current use or recommended use of artificial tears for the treatment of Dry Eye)

    9. Best corrected distance visual acuity (BCDVA) score of ≥ 0.1 decimal units (20/200 Snellen value) in both eyes at the time of study enrolment

    10. If a female of childbearing potential, have a negative pregnancy test

    11. Only patients who satisfy all Informed Consent requirements may be included in the study. The patient and/or his/her legal representative must read, sign and date the Informed Consent document before any study-related procedures are performed. The Informed Consent form signed by patients and/or legal representative must have been approved by the Institutional Review Board (IRB) / Independent Ethics Committee (IEC) for the current study

    12. Patients must have the ability and willingness to comply with study procedures.

    Exclusion Criteria:
    1. Inability to speak and understand the local language sufficiently to understand the nature of the study, to provide written informed consent, and to allow the completion of all study assessments;

    2. Evidence of an active ocular infection, in either eye

    3. Presence of any other ocular disorder or condition requiring topical medication during the entire duration of study

    4. History of severe systemic allergy or of ocular allergy (including seasonal conjunctivitis) or chronic conjunctivitis and/or keratitis other than dry eye

    5. Intraocular inflammation defined as Tyndall score >0

    6. History of malignancy in the last 5 years

    7. Systemic disease not stabilized within 1 month before Screening Visit (e.g. diabetes with glycemia out of range, thyroid malfunction..) or judged by the investigator to be incompatible with the study (e.g. current systemic infections) or with a condition incompatible with the frequent assessment required by the study

    8. Patient had a serious adverse reaction or significant hypersensitivity to any drug or chemically related compounds or had a clinically significant allergy to drugs, foods, amide local anaesthetics or other materials including commercial artificial tears (in the opinion of the investigator)

    9. Females of childbearing potential (those who are not surgically sterilized or post-menopausal for at least 1 year) are excluded from participation in the study if they meet any one of the following conditions:

    10. are currently pregnant or,

    11. have a positive result at the urine pregnancy test (Baseline/Day 0) or,

    12. intend to become pregnant during the study treatment period or,

    13. are breast-feeding or,

    14. are not willing to use highly effective birth control measures, such as: hormonal contraceptives - oral, implanted, transdermal, or injected - and/or mechanical barrier methods - spermicide in conjunction with a barrier such as a condom or diaphragm or Intra Uterine Device (IUD) - during the entire course of and 30 days after the study treatment periods

    15. Any concurrent medical condition, that in the judgment of the PI, might interfere with the conduct of the study, confound the interpretation of the study results, or endanger the patient's well-being

    16. Use of topical cyclosporine, topical corticosteroids or any other topical drug for the treatment of dry eye in either eye within 30 days of study enrolment.

    17. Contact lenses or punctum plug use during the study (previous use not an exclusion criteria but must be discontinued at the screening visit)

    18. History of drug addiction or alcohol abuse

    19. Any prior ocular surgery (including refractive palpebral and cataract surgery) if within 90 days before the screening visit

    20. Participation in a clinical trial with a new active substance during the past 6 months

    21. Participation in another clinical trial study at the same time as the present study.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Global Research Management Glendale California United States 91204
    2 Eye Research Foundation Newport Beach California United States 92663
    3 Martel Eye Medical Group Rancho Cordova California United States 95670
    4 Sierra Clinical Trials & Research Organization Santa Ana California United States 92647
    5 Clayton Eye Clinical Research, LLC Morrow Georgia United States 30260
    6 Kentucky Eye Institute Lexington Kentucky United States 40517
    7 Tauber Eye Center Kansas City Missouri United States 64111
    8 Moyes Eye Center Kansas City Missouri United States 64154
    9 SightMD Babylon New York United States 11702
    10 Toyos Clinic Nashville Tennessee United States 37027
    11 Houston Eye Associates HEA - Gramercy Location Houston Texas United States 77025
    12 Advanced Laser Vision Surgical Institute (Study Site) Intouch Clinical Research Center (SMO) Houston Texas United States 77034

    Sponsors and Collaborators

    • Dompé Farmaceutici S.p.A

    Investigators

    • Study Director: Flavio Mantelli, MD, Dompé Farmaceutici SpA
    • Principal Investigator: William Lipsky, MD, Advanced Laser Vision Surgical Institute (Study Site) Intouch Clinical Research Center (SMO)

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Dompé Farmaceutici S.p.A
    ClinicalTrials.gov Identifier:
    NCT03982368
    Other Study ID Numbers:
    • NGF0118
    First Posted:
    Jun 11, 2019
    Last Update Posted:
    Feb 8, 2022
    Last Verified:
    Jan 1, 2022
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail Enrollment of a total of 300 patients was planned. Due to restrictions in the hospital clinical routines related to coronavirus disease 2019, the sponsor decided to prematurely stop enrollment in the study in order to comply with quarantine measures of each country and avoid risks of infection of COVID-19 illness for all involved patients. A total of 261 patients were randomized to receive study treatment: 87 in the rhNGF TID group, 86 in the rhNGF BID group, and 88 in the vehicle TID group.
    Arm/Group Title rhNGF 20 μg/ml TID rhNGF 20 μg/ml BID + Vehicle OD Vehicle TID
    Arm/Group Description One drop of rhNGF 20 μg/ml will be instilled in both eyes three times daily (every 6-8 hours) rhNGF 20 μg/ml: one drop of rhNGF 20 μg/ml will be instilled in both eyes three times daily (every 6-8 hours) One drop of rhNGF 20 μg/ml will be instilled in both eyes two times daily (BID) plus one drop (40 μL) of vehicle will be instilled in both eyes once daily (OD) (every 6-8 hours) rhNGF 20 μg/ml + vehicle: one drop of rhNGF 20 μg/ml will be instilled in both eyes two times daily plus one drop (40 μL) of vehicle will be instilled in both eyes once daily (every 6-8 hours). rhNGF will be instilled in the morning and in the evening while the vehicle will be instilled in the afternoon. Vehicle eye one drop will be instilled in both eyes three times daily (every 6-8 hours) Vehicle: one drop of vehicle will be instilled in both eyes three times daily (every 6-8 hours)
    Period Title: Overall Study
    STARTED 87 86 88
    FAS Popuation 81 82 84
    PP Population 72 71 80
    COMPLETED 74 79 83
    NOT COMPLETED 13 7 5

    Baseline Characteristics

    Arm/Group Title rhNGF 20 μg/ml TID rhNGF 20 μg/ml BID + Vehicle OD Vehicle TID Total
    Arm/Group Description One drop of rhNGF 20 μg/ml will be instilled in both eyes three times daily (every 6-8 hours) rhNGF 20 μg/ml: one drop of rhNGF 20 μg/ml will be instilled in both eyes three times daily (every 6-8 hours) One drop of rhNGF 20 μg/ml will be instilled in both eyes two times daily (BID) plus one drop (40 μL) of vehicle will be instilled in both eyes once daily (OD) (every 6-8 hours) rhNGF 20 μg/ml + vehicle: one drop of rhNGF 20 μg/ml will be instilled in both eyes two times daily plus one drop (40 μL) of vehicle will be instilled in both eyes once daily (every 6-8 hours). rhNGF will be instilled in the morning and in the evening while the vehicle will be instilled in the afternoon. Vehicle eye one drop will be instilled in both eyes three times daily (every 6-8 hours) Vehicle: one drop of vehicle will be instilled in both eyes three times daily (every 6-8 hours) Total of all reporting groups
    Overall Participants 81 82 84 247
    Age (Count of Participants)
    <=18 years
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Between 18 and 65 years
    51
    63%
    54
    65.9%
    61
    72.6%
    166
    67.2%
    >=65 years
    30
    37%
    28
    34.1%
    23
    27.4%
    81
    32.8%
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    62.0
    (13.52)
    60.2
    (12.39)
    59.1
    (11.50)
    60.4
    (12.49)
    Sex: Female, Male (Count of Participants)
    Female
    57
    70.4%
    69
    84.1%
    72
    85.7%
    198
    80.2%
    Male
    24
    29.6%
    13
    15.9%
    12
    14.3%
    49
    19.8%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    15
    18.5%
    9
    11%
    13
    15.5%
    37
    15%
    Not Hispanic or Latino
    66
    81.5%
    73
    89%
    71
    84.5%
    210
    85%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Region of Enrollment (participants) [Number]
    United States
    81
    100%
    82
    100%
    84
    100%
    247
    100%

    Outcome Measures

    1. Primary Outcome
    Title Change From Baseline in Schirmer I Test (Without Anesthesia) vs Week 4 - Full Analysis Set
    Description The Schirmer test is used in ophthalmic examination to measure tear production for the diagnosis of conditions such as keratoconjunctivitis sicca and dry eye. Without previously instilling anesthetic drops, the Schirmer strip is inserted into the lower conjunctival sac at the junction of the lateral and middle thirds, avoiding touching the cornea, and the length of wetting strips in millimeters is recorded after 5 minutes. The patients will be instructed to close their eyes gently. After 5 minutes have elapsed, the Schirmer test strip will be removed and the length of the tear absorption on the strip will be measured (millimeters/5 minutes) Cutoff values: <5 mm - pathologic dry eye 5-10 mm - marginal dry eye >10 and <30 mm - normal secretion
    Time Frame Baseline, week 4

    Outcome Measure Data

    Analysis Population Description
    Full analysis set (FAS): The FAS consisted of all patients randomized who took at least 1 dose of IMP and who had at least 1 postbaseline efficacy measurement for the primary endpoint.
    Arm/Group Title rhNGF 20 μg/ml TID rhNGF 20 μg/ml BID + Vehicle OD Vehicle TID
    Arm/Group Description One drop of rhNGF 20 μg/ml will be instilled in both eyes three times daily (every 6-8 hours) rhNGF 20 μg/ml: one drop of rhNGF 20 μg/ml will be instilled in both eyes three times daily (every 6-8 hours) One drop of rhNGF 20 μg/ml will be instilled in both eyes two times daily (BID) plus one drop (40 μL) of vehicle will be instilled in both eyes once daily (OD) (every 6-8 hours) rhNGF 20 μg/ml + vehicle: one drop of rhNGF 20 μg/ml will be instilled in both eyes two times daily plus one drop (40 μL) of vehicle will be instilled in both eyes once daily (every 6-8 hours). rhNGF will be instilled in the morning and in the evening while the vehicle will be instilled in the afternoon. Vehicle eye one drop will be instilled in both eyes three times daily (every 6-8 hours) Vehicle: one drop of vehicle will be instilled in both eyes three times daily (every 6-8 hours)
    Measure Participants 81 82 84
    Least Squares Mean (Standard Error) [mm]
    2.60
    (0.77)
    3.99
    (0.76)
    1.68
    (0.75)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments The primary endpoint was analyzed using analysis of variance (ANOVA) including only treatment as the main factor, followed by preplanned comparisons from vehicle and rhNGF dosages according to Williams' procedure.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.078
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter least square mean difference
    Estimated Value 0.93
    Confidence Interval (2-Sided) 95%
    -1.47 to 3.32
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments The primary endpoint was analyzed using analysis of variance (ANOVA) including only treatment as the main factor, followed by preplanned comparisons from vehicle and rhNGF dosages according to Williams' procedure.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.066
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter least square mean difference
    Estimated Value 2.31
    Confidence Interval (2-Sided) 95%
    -0.08 to 4.70
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Primary Outcome
    Title Change From Baseline in Schirmer I Test (Without Anesthesia) vs Week 4 - Per Protocol Set
    Description The Schirmer test is used in ophthalmic examination to measure tear production for the diagnosis of conditions such as keratoconjunctivitis sicca and dry eye. Without previously instilling anesthetic drops, the Schirmer strip is inserted into the lower conjunctival sac at the junction of the lateral and middle thirds, avoiding touching the cornea, and the length of wetting strips in millimeters is recorded after 5 minutes. The patients will be instructed to close their eyes gently. After 5 minutes have elapsed, the Schirmer test strip will be removed and the length of the tear absorption on the strip will be measured (millimeters/5 minutes) Cutoff values: <5 mm - pathologic dry eye 5-10 mm - marginal dry eye >10 and <30 mm - normal secretion
    Time Frame Baseline, week 4

    Outcome Measure Data

    Analysis Population Description
    Per protocol (PP) set: The PP set consisted of all patients in the FAS who fulfilled the study protocol requirements in terms of IMP intake and collection of primary efficacy data and had no major deviations that may have affected study results.
    Arm/Group Title rhNGF 20 μg/ml TID rhNGF 20 μg/ml BID + Vehicle OD Vehicle TID
    Arm/Group Description One drop of rhNGF 20 μg/ml will be instilled in both eyes three times daily (every 6-8 hours) rhNGF 20 μg/ml: one drop of rhNGF 20 μg/ml will be instilled in both eyes three times daily (every 6-8 hours) One drop of rhNGF 20 μg/ml will be instilled in both eyes two times daily (BID) plus one drop (40 μL) of vehicle will be instilled in both eyes once daily (OD) (every 6-8 hours) rhNGF 20 μg/ml + vehicle: one drop of rhNGF 20 μg/ml will be instilled in both eyes two times daily plus one drop (40 μL) of vehicle will be instilled in both eyes once daily (every 6-8 hours). rhNGF will be instilled in the morning and in the evening while the vehicle will be instilled in the afternoon. Vehicle eye one drop will be instilled in both eyes three times daily (every 6-8 hours) Vehicle: one drop of vehicle will be instilled in both eyes three times daily (every 6-8 hours)
    Measure Participants 72 71 80
    Least Squares Mean (Standard Error) [mm]
    2.99
    (0.78)
    3.72
    (0.79)
    1.28
    (0.74)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.032
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 1.71
    Confidence Interval (2-Sided) 95%
    -0.70 to 4.12
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.029
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 2.44
    Confidence Interval (2-Sided) 95%
    0.02 to 4.86
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    3. Secondary Outcome
    Title Change From Baseline in Symptoms Questionnaire (SANDE) Scores for Severity vs Week 4 - Full Analysis Set
    Description The SANDE (symptom assessment in dry eye) score is composed by two questions presented in visual analog scale. The two questions assess the frequency and severity of dry eye syndrome. The global score is calculated by taking the square root of the product of the severity of symptoms per the frequency of symptoms. The SANDE scale ranges from 0 to 100 with 100 being the maximal amount of dry eye symptoms and 0 being the minimal amount of dry eye symptoms.
    Time Frame Baseline, week 4

    Outcome Measure Data

    Analysis Population Description
    Full analysis set (FAS): The FAS consisted of all patients randomized who took at least 1 dose of IMP and who had at least 1 postbaseline efficacy measurement for the primary endpoint.
    Arm/Group Title rhNGF 20 μg/ml TID rhNGF 20 μg/ml BID + Vehicle OD Vehicle TID
    Arm/Group Description One drop of rhNGF 20 μg/ml will be instilled in both eyes three times daily (every 6-8 hours) rhNGF 20 μg/ml: one drop of rhNGF 20 μg/ml will be instilled in both eyes three times daily (every 6-8 hours) One drop of rhNGF 20 μg/ml will be instilled in both eyes two times daily (BID) plus one drop (40 μL) of vehicle will be instilled in both eyes once daily (OD) (every 6-8 hours) rhNGF 20 μg/ml + vehicle: one drop of rhNGF 20 μg/ml will be instilled in both eyes two times daily plus one drop (40 μL) of vehicle will be instilled in both eyes once daily (every 6-8 hours). rhNGF will be instilled in the morning and in the evening while the vehicle will be instilled in the afternoon. Vehicle eye one drop will be instilled in both eyes three times daily (every 6-8 hours) Vehicle: one drop of vehicle will be instilled in both eyes three times daily (every 6-8 hours)
    Measure Participants 81 82 84
    Mean (Standard Deviation) [score on a scale]
    -24.6
    (27.15)
    -20.3
    (24.91)
    -22.2
    (22.29)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.534
    Comments
    Method t-test, 2 sided
    Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.611
    Comments
    Method t-test, 2 sided
    Comments
    4. Secondary Outcome
    Title Change From Baseline in Symptoms Questionnaire (SANDE) Scores for Severity vs Week 4 - Per Protocol Set
    Description The SANDE (symptom assessment in dry eye) score is composed by two questions presented in visual analog scale. The two questions assess the frequency and severity of dry eye syndrome. The global score is calculated by taking the square root of the product of the severity of symptoms per the frequency of symptoms. The SANDE scale ranges from 0 to 100 with 100 being the maximal amount of dry eye symptoms and 0 being the minimal amount of dry eye symptoms.
    Time Frame Baseline, week 4

    Outcome Measure Data

    Analysis Population Description
    Per protocol (PP) set: The PP set consisted of all patients in the FAS who fulfilled the study protocol requirements in terms of IMP intake and collection of primary efficacy data and had no major deviations that may have affected study results.
    Arm/Group Title rhNGF 20 μg/ml TID rhNGF 20 μg/ml BID + Vehicle OD Vehicle TID
    Arm/Group Description One drop of rhNGF 20 μg/ml will be instilled in both eyes three times daily (every 6-8 hours) rhNGF 20 μg/ml: one drop of rhNGF 20 μg/ml will be instilled in both eyes three times daily (every 6-8 hours) One drop of rhNGF 20 μg/ml will be instilled in both eyes two times daily (BID) plus one drop (40 μL) of vehicle will be instilled in both eyes once daily (OD) (every 6-8 hours) rhNGF 20 μg/ml + vehicle: one drop of rhNGF 20 μg/ml will be instilled in both eyes two times daily plus one drop (40 μL) of vehicle will be instilled in both eyes once daily (every 6-8 hours). rhNGF will be instilled in the morning and in the evening while the vehicle will be instilled in the afternoon. Vehicle eye one drop will be instilled in both eyes three times daily (every 6-8 hours) Vehicle: one drop of vehicle will be instilled in both eyes three times daily (every 6-8 hours)
    Measure Participants 72 71 80
    Mean (Standard Deviation) [score on a scale]
    -24.9
    (27.35)
    -19.9
    (25.34)
    -22.1
    (21.74)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.486
    Comments
    Method t-test, 2 sided
    Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.564
    Comments
    Method t-test, 2 sided
    Comments
    5. Secondary Outcome
    Title Change From Baseline in Symptoms Questionnaire (SANDE) Scores for Frequency vs Week 4 - Full Analysis Set
    Description The SANDE (symptom assessment in dry eye) score is composed by two questions presented in visual analog scale. The two questions assess the frequency and severity of dry eye syndrome.The SANDE global score is calculated by taking the square root of the product of the frequency of symptoms and the severity of symptoms. The SANDE scale ranges from 0 to 100 wi.100 being the maximal amount of dry eye symptoms and 0 being the minimal amount of dry eye symptoms
    Time Frame Baseline, week 4

    Outcome Measure Data

    Analysis Population Description
    Full analysis set (FAS): The FAS consisted of all patients randomized who took at least 1 dose of IMP and who had at least 1 postbaseline efficacy measurement for the primary endpoint.
    Arm/Group Title rhNGF 20 μg/ml TID rhNGF 20 μg/ml BID + Vehicle OD Vehicle TID
    Arm/Group Description One drop of rhNGF 20 μg/ml will be instilled in both eyes three times daily (every 6-8 hours) rhNGF 20 μg/ml: one drop of rhNGF 20 μg/ml will be instilled in both eyes three times daily (every 6-8 hours) One drop of rhNGF 20 μg/ml will be instilled in both eyes two times daily (BID) plus one drop (40 μL) of vehicle will be instilled in both eyes once daily (OD) (every 6-8 hours) rhNGF 20 μg/ml + vehicle: one drop of rhNGF 20 μg/ml will be instilled in both eyes two times daily plus one drop (40 μL) of vehicle will be instilled in both eyes once daily (every 6-8 hours). rhNGF will be instilled in the morning and in the evening while the vehicle will be instilled in the afternoon. Vehicle eye one drop will be instilled in both eyes three times daily (every 6-8 hours) Vehicle: one drop of vehicle will be instilled in both eyes three times daily (every 6-8 hours)
    Measure Participants 81 82 84
    Mean (Standard Deviation) [score on a scale]
    -24.9
    (26.29)
    -22.7
    (25.42)
    -24.0
    (23.81)
    6. Secondary Outcome
    Title Change From Baseline in Symptoms Questionnaire (SANDE) Scores for Frequency vs Week 4 - Per Protocol Set
    Description The SANDE (symptom assessment in dry eye) score is composed by two questions presented in visual analog scale. The two questions assess the frequency and severity of dry eye syndrome. The SANDE score is calculated by taking the square root of the product of the frequency of symptoms score. The SANDE scale ranges from 0 to 100 wi.100 being the maximal amount of dry eye symptoms and 0 being the minimal amount of dry eye symptoms.
    Time Frame Baseline, week 4

    Outcome Measure Data

    Analysis Population Description
    Per protocol (PP) set: The PP set consisted of all patients in the FAS who fulfilled the study protocol requirements in terms of IMP intake and collection of primary efficacy data and had no major deviations that may have affected study results.
    Arm/Group Title rhNGF 20 μg/ml TID rhNGF 20 μg/ml BID + Vehicle OD Vehicle TID
    Arm/Group Description One drop of rhNGF 20 μg/ml will be instilled in both eyes three times daily (every 6-8 hours) rhNGF 20 μg/ml: one drop of rhNGF 20 μg/ml will be instilled in both eyes three times daily (every 6-8 hours) One drop of rhNGF 20 μg/ml will be instilled in both eyes two times daily (BID) plus one drop (40 μL) of vehicle will be instilled in both eyes once daily (OD) (every 6-8 hours) rhNGF 20 μg/ml + vehicle: one drop of rhNGF 20 μg/ml will be instilled in both eyes two times daily plus one drop (40 μL) of vehicle will be instilled in both eyes once daily (every 6-8 hours). rhNGF will be instilled in the morning and in the evening while the vehicle will be instilled in the afternoon. Vehicle eye one drop will be instilled in both eyes three times daily (every 6-8 hours) Vehicle: one drop of vehicle will be instilled in both eyes three times daily (every 6-8 hours)
    Measure Participants 72 71 80
    Mean (Standard Deviation) [score on a scale]
    -24.7
    (26.73)
    -22.2
    (25.67)
    -23.8
    (23.92)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.810
    Comments
    Method t-test, 2 sided
    Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.733
    Comments
    Method t-test, 2 sided
    Comments
    7. Secondary Outcome
    Title Change From Baseline in Schirmer II Test (With Anesthesia) vs Week 4 - Full Analysis Set
    Description The Schirmer II test is performed as the Schirmer I test after instilling anesthetic drops. The Schirmer strips are inserted into the lower conjunctival sac at the junction of the lateral and middle thirds, avoiding touching the cornea, and the length of wetting strips in millimeters is recorded after 5 minutes. All patients are seated at rest with their eyes closed, and the lower cul-de-sac is gently dried with a cotton applicator before the placement of strips. Cut-off values: <5 mm - pathologic dry eye 5-10 mm - marginal dry eye >10 and <30 mm - normal secretion
    Time Frame Baseline, week 4

    Outcome Measure Data

    Analysis Population Description
    Full analysis set (FAS): The FAS consisted of all patients randomized who took at least 1 dose of IMP and who had at least 1 postbaseline efficacy measurement for the primary endpoint.
    Arm/Group Title rhNGF 20 μg/ml TID rhNGF 20 μg/ml BID + Vehicle OD Vehicle TID
    Arm/Group Description One drop of rhNGF 20 μg/ml will be instilled in both eyes three times daily (every 6-8 hours) rhNGF 20 μg/ml: one drop of rhNGF 20 μg/ml will be instilled in both eyes three times daily (every 6-8 hours) One drop of rhNGF 20 μg/ml will be instilled in both eyes two times daily (BID) plus one drop (40 μL) of vehicle will be instilled in both eyes once daily (OD) (every 6-8 hours) rhNGF 20 μg/ml + vehicle: one drop of rhNGF 20 μg/ml will be instilled in both eyes two times daily plus one drop (40 μL) of vehicle will be instilled in both eyes once daily (every 6-8 hours). rhNGF will be instilled in the morning and in the evening while the vehicle will be instilled in the afternoon. Vehicle eye one drop will be instilled in both eyes three times daily (every 6-8 hours) Vehicle: one drop of vehicle will be instilled in both eyes three times daily (every 6-8 hours)
    Measure Participants 81 82 84
    Least Squares Mean (Standard Error) [mm]
    2.19
    (0.69)
    0.89
    (0.69)
    0.21
    (0.68)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments The secondary endpoint was analyzed using analysis of variance (ANOVA) including only treatment as the main factor, followed by preplanned comparisons from vehicle and rhNGF dosages according to Williams' procedure.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.025
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 1.97
    Confidence Interval (2-Sided) 95%
    -0.19 to 4.13
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments The secondary endpoint was analyzed using analysis of variance (ANOVA) including only treatment as the main factor, followed by preplanned comparisons from vehicle and rhNGF dosages according to Williams' procedure.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.243
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 0.68
    Confidence Interval (2-Sided) 95%
    -1.48 to 2.83
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    8. Secondary Outcome
    Title Change From Baseline in Schirmer II Test (With Anesthesia) vs Week 4 - Per Protocol Set
    Description The Schirmer II test is performed as the Schirmer I test after instilling anesthetic drops. The Schirmer strips are inserted into the lower conjunctival sac at the junction of the lateral and middle thirds, avoiding touching the cornea, and the length of wetting strips in millimeters is recorded after 5 minutes. All patients are seated at rest with their eyes closed, and the lower cul-de-sac is gently dried with a cotton applicator before the placement of strips. Cut-off values: <5 mm - pathologic dry eye 5-10 mm - marginal dry eye >10 and <30 mm - normal secretion
    Time Frame Baseline, week 4

    Outcome Measure Data

    Analysis Population Description
    Per protocol (PP) set: The PP set consisted of all patients in the FAS who fulfilled the study protocol requirements in terms of IMP intake and collection of primary efficacy data and had no major deviations that may have affected study results.
    Arm/Group Title rhNGF 20 μg/ml TID rhNGF 20 μg/ml BID + Vehicle OD Vehicle TID
    Arm/Group Description One drop of rhNGF 20 μg/ml will be instilled in both eyes three times daily (every 6-8 hours) rhNGF 20 μg/ml: one drop of rhNGF 20 μg/ml will be instilled in both eyes three times daily (every 6-8 hours) One drop of rhNGF 20 μg/ml will be instilled in both eyes two times daily (BID) plus one drop (40 μL) of vehicle will be instilled in both eyes once daily (OD) (every 6-8 hours) rhNGF 20 μg/ml + vehicle: one drop of rhNGF 20 μg/ml will be instilled in both eyes two times daily plus one drop (40 μL) of vehicle will be instilled in both eyes once daily (every 6-8 hours). rhNGF will be instilled in the morning and in the evening while the vehicle will be instilled in the afternoon. Vehicle eye one drop will be instilled in both eyes three times daily (every 6-8 hours) Vehicle: one drop of vehicle will be instilled in both eyes three times daily (every 6-8 hours)
    Measure Participants 72 71 80
    Least Squares Mean (Standard Error) [mm]
    2.24
    (0.69)
    0.54
    (0.70)
    -0.18
    (0.66)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.007
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 2.41
    Confidence Interval (2-Sided) 95%
    0.28 to 4.54
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.230
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 0.71
    Confidence Interval (2-Sided) 95%
    -1.43 to 2.85
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    9. Secondary Outcome
    Title Change From Baseline in Corneal and Conjunctiva Vital Staining With Fluorescein (National Eye Institute [NEI] Scales) vs Week 4 - Full Analysis Set
    Description Corneal staining total score is defined as the sum of scores from 5 corneal areas: Central, Superior, Temporal, Nasal, and Inferior. The score for each area ranges from 0 to 3 where grade 0 reflects normal/healthy situation, whereas grade 3 reflects a severe damage. Thus, the corneal staining total score can range from 0 to 15 where the higher the score the worse is the outcome. The conjunctiva is divided into a superior paralimbal area, an inferior paralimbal area and a peripheral area with a grading scale of 0-3 where grade 0 reflects normal/healthy situation, whereas grade 3 reflects a severe damage and with a maximal score of 9 for the nasal and temporal conjunctiva. Thus, the conjunctival staining total score can range from 0 to 18 where the higher the score the worse is the outcome. Corneal and conjunctiva vital staining total score is the sum of corneal staining total score and conjunctiva total score.
    Time Frame Baseline, week 4

    Outcome Measure Data

    Analysis Population Description
    Full analysis set (FAS): The FAS consisted of all patients randomized who took at least 1 dose of IMP and who had at least 1 postbaseline efficacy measurement for the primary endpoint.
    Arm/Group Title rhNGF 20 μg/ml TID rhNGF 20 μg/ml BID + Vehicle OD Vehicle TID
    Arm/Group Description One drop of rhNGF 20 μg/ml will be instilled in both eyes three times daily (every 6-8 hours) rhNGF 20 μg/ml: one drop of rhNGF 20 μg/ml will be instilled in both eyes three times daily (every 6-8 hours) One drop of rhNGF 20 μg/ml will be instilled in both eyes two times daily (BID) plus one drop (40 μL) of vehicle will be instilled in both eyes once daily (OD) (every 6-8 hours) rhNGF 20 μg/ml + vehicle: one drop of rhNGF 20 μg/ml will be instilled in both eyes two times daily plus one drop (40 μL) of vehicle will be instilled in both eyes once daily (every 6-8 hours). rhNGF will be instilled in the morning and in the evening while the vehicle will be instilled in the afternoon. Vehicle eye one drop will be instilled in both eyes three times daily (every 6-8 hours) Vehicle: one drop of vehicle will be instilled in both eyes three times daily (every 6-8 hours)
    Measure Participants 81 82 84
    corneal and conjunctival total score
    -3.75
    (0.63)
    -2.95
    (0.62)
    -2.60
    (0.61)
    corneal score
    -1.9
    (2.84)
    -1.8
    (2.72)
    -1.5
    (2.92)
    conjunctiva score
    -2.1
    (3.17)
    -1.2
    (3.58)
    -1.4
    (3.36)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments The secondary endpoint was analyzed using analysis of variance (ANOVA) including only treatment as the main factor, followed by preplanned comparisons from vehicle and rhNGF dosages according to Williams' procedure. p value for total corneal ancd conjunctival score is reported.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.799
    Comments
    Method ANOVA
    Comments Last Observation Carried Forward (LOCF) was used for imputing missing data in the Full analysis set at Week 4.
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value -1.16
    Confidence Interval (2-Sided) 95%
    -3.11 to 0.80
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments The secondary endpoint was analyzed using analysis of variance (ANOVA) including only treatment as the main factor, followed by preplanned comparisons from vehicle and rhNGF dosages according to Williams' procedure.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.715
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value -0.36
    Confidence Interval (2-Sided) 95%
    -2.30 to 1.59
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    10. Secondary Outcome
    Title Change From Baseline in Corneal and Conjunctiva Vital Staining With Fluorescein (National Eye Institute [NEI] Scales) vs Week 4 - Per Protocol Set
    Description Corneal staining total score is defined as the sum of scores from 5 corneal areas: Central, Superior, Temporal, Nasal, and Inferior. The score for each area ranges from 0 to 3 where grade 0 reflects normal/healthy situation, whereas grade 3 reflects a severe damage. Thus, the corneal staining total score can range from 0 to 15 where the higher the score the worse is the outcome. The conjunctiva is divided into a superior paralimbal area, an inferior paralimbal area and a peripheral area with a grading scale of 0-3 where grade 0 reflects normal/healthy situation, whereas grade 3 reflects a severe damage and with a maximal score of 9 for the nasal and temporal conjunctiva. Thus, the conjunctival staining total score can range from 0 to 18 where the higher the score the worse is the outcome. Corneal and conjunctiva vital staining total score is the sum of corneal staining total score and conjunctiva total score.
    Time Frame Baseline, week 4

    Outcome Measure Data

    Analysis Population Description
    Per protocol (PP) set: The PP set consisted of all patients in the FAS who fulfilled the study protocol requirements in terms of IMP intake and collection of primary efficacy data and had no major deviations that may have affected study results. This analysis set was used for supportive efficacy analysis.
    Arm/Group Title rhNGF 20 μg/ml TID rhNGF 20 μg/ml BID + Vehicle OD Vehicle TID
    Arm/Group Description One drop of rhNGF 20 μg/ml will be instilled in both eyes three times daily (every 6-8 hours) rhNGF 20 μg/ml: one drop of rhNGF 20 μg/ml will be instilled in both eyes three times daily (every 6-8 hours) One drop of rhNGF 20 μg/ml will be instilled in both eyes two times daily (BID) plus one drop (40 μL) of vehicle will be instilled in both eyes once daily (OD) (every 6-8 hours) rhNGF 20 μg/ml + vehicle: one drop of rhNGF 20 μg/ml will be instilled in both eyes two times daily plus one drop (40 μL) of vehicle will be instilled in both eyes once daily (every 6-8 hours). rhNGF will be instilled in the morning and in the evening while the vehicle will be instilled in the afternoon. Vehicle eye one drop will be instilled in both eyes three times daily (every 6-8 hours) Vehicle: one drop of vehicle will be instilled in both eyes three times daily (every 6-8 hours)
    Measure Participants 72 71 80
    Total score
    -3.94
    (0.60)
    -2.61
    (0.61)
    -2.40
    (0.57)
    Corneal score
    -1.9
    (2.80)
    -1.8
    (2.61)
    -1.5
    (2.85)
    Conjunctival score
    -1.9
    (2.95)
    -1.0
    (3.05)
    -1.3
    (3.32)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments The secondary endpoint was analyzed using analysis of variance (ANOVA) including only treatment as the main factor, followed by preplanned comparisons from vehicle and rhNGF dosages according to Williams' procedure. p value for total corneal ancd conjunctival score is reported.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.831
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value -1.54
    Confidence Interval (2-Sided) 95%
    -3.40 to 0.31
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments The secondary endpoint was analyzed using analysis of variance (ANOVA) including only treatment as the main factor, followed by preplanned comparisons from vehicle and rhNGF dosages according to Williams' procedure. p value for total corneal ancd conjunctival score is reported.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.750
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value -0.21
    Confidence Interval (2-Sided) 95%
    -2.07 to 1.66
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    11. Secondary Outcome
    Title Change From Baseline in Tear Film Break-Up Time (TFBUT) vs Week 4 - Full Analysis Set
    Description Tear film break-up time (TFBUT) is the time taken to appear first dry spot on cornea after a complete blinking. TFBUT measurement is an easy and fast method used to assess the stability of tear film. It is a standard diagnostic procedure in the dry eye clinics. TFBUT is measured by determining the time to tear break-up. The TFBUT is performed after instillation of 5 μL of 2% preservative-free sodium fluorescein solution into the inferior conjunctival cul-de-sac of each eye. The patient is instructed to blink several times to thoroughly mix the fluorescein with the tear film. A TFBUT greater than 15 seconds is considered normal, while a break time of less than 10 seconds is to be considered pathological.
    Time Frame Baseline, week 4

    Outcome Measure Data

    Analysis Population Description
    Full analysis set (FAS): The FAS consisted of all patients randomized who took at least 1 dose of IMP and who had at least 1 postbaseline efficacy measurement for the primary endpoint.
    Arm/Group Title rhNGF 20 μg/ml TID rhNGF 20 μg/ml BID + Vehicle OD Vehicle TID
    Arm/Group Description One drop of rhNGF 20 μg/ml will be instilled in both eyes three times daily (every 6-8 hours) rhNGF 20 μg/ml: one drop of rhNGF 20 μg/ml will be instilled in both eyes three times daily (every 6-8 hours) One drop of rhNGF 20 μg/ml will be instilled in both eyes two times daily (BID) plus one drop (40 μL) of vehicle will be instilled in both eyes once daily (OD) (every 6-8 hours) rhNGF 20 μg/ml + vehicle: one drop of rhNGF 20 μg/ml will be instilled in both eyes two times daily plus one drop (40 μL) of vehicle will be instilled in both eyes once daily (every 6-8 hours). rhNGF will be instilled in the morning and in the evening while the vehicle will be instilled in the afternoon. Vehicle eye one drop will be instilled in both eyes three times daily (every 6-8 hours) Vehicle: one drop of vehicle will be instilled in both eyes three times daily (every 6-8 hours)
    Measure Participants 81 82 84
    Least Squares Mean (Standard Error) [seconds]
    1.11
    (0.25)
    0.43
    (0.25)
    0.15
    (0.25)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.004
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 0.96
    Confidence Interval (2-Sided) 95%
    0.17 to 1.75
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.217
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 0.28
    Confidence Interval (2-Sided) 95%
    -0.51 to 1.07
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    12. Secondary Outcome
    Title Change From Baseline in Tear Film Break-Up Time (TFBUT) vs Week 4 - Per Protocol Set
    Description Tear film break-up time (TFBUT) is the time taken to appear first dry spot on cornea after a complete blinking. TFBUT measurement is an easy and fast method used to assess the stability of tear film. It is a standard diagnostic procedure in the dry eye clinics. TFBUT is measured by determining the time to tear break-up. The TFBUT is performed after instillation of 5 μL of 2% preservative-free sodium fluorescein solution into the inferior conjunctival cul-de-sac of each eye. The patient is instructed to blink several times to thoroughly mix the fluorescein with the tear film. A TFBUT greater than 15 seconds is considered normal, while a break time of less than 10 seconds is to be considered pathological.
    Time Frame Baseline, week 4

    Outcome Measure Data

    Analysis Population Description
    Per protocol (PP) set: The PP set consisted of all patients in the FAS who fulfilled the study protocol requirements in terms of IMP intake and collection of primary efficacy data and had no major deviations that may have affected study results.
    Arm/Group Title rhNGF 20 μg/ml TID rhNGF 20 μg/ml BID + Vehicle OD Vehicle TID
    Arm/Group Description One drop of rhNGF 20 μg/ml will be instilled in both eyes three times daily (every 6-8 hours) rhNGF 20 μg/ml: one drop of rhNGF 20 μg/ml will be instilled in both eyes three times daily (every 6-8 hours) One drop of rhNGF 20 μg/ml will be instilled in both eyes two times daily (BID) plus one drop (40 μL) of vehicle will be instilled in both eyes once daily (OD) (every 6-8 hours) rhNGF 20 μg/ml + vehicle: one drop of rhNGF 20 μg/ml will be instilled in both eyes two times daily plus one drop (40 μL) of vehicle will be instilled in both eyes once daily (every 6-8 hours). rhNGF will be instilled in the morning and in the evening while the vehicle will be instilled in the afternoon. Vehicle eye one drop will be instilled in both eyes three times daily (every 6-8 hours) Vehicle: one drop of vehicle will be instilled in both eyes three times daily (every 6-8 hours)
    Measure Participants 72 71 80
    Least Squares Mean (Standard Error) [seconds]
    1.11
    (0.27)
    0.47
    (0.27)
    0.19
    (0.25)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.007
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 0.92
    Confidence Interval (2-Sided) 95%
    0.10 to 1.74
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.225
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 0.28
    Confidence Interval (2-Sided) 95%
    -0.54 to 1.10
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    13. Secondary Outcome
    Title Number of Patients Who Experienced a Worsening in Symptom Scores (SANDE) and/or NEI Score ≥ 50% Assessed at Week 4 - Full Analysis Set
    Description The SANDE score is calculated by taking the square root of the product of the severity of symptoms score. The SANDE scale ranges from 0 to 100 with 100 being the maximal amount of dry eye symptoms and 0 being the minimal amount of dry eye symptoms. The NEI/Industry Workshop guidelines are used for grading the scale of corneal and conjunctival damage. The cornea is divided into five sectors (central, superior, inferior, nasal and temporal), each of which is scored on a scale of 0-3, with a maximal total corneal staining score of 15. Both nasally and temporally, the conjunctiva is divided into a superior paralimbal area, an inferior paralimbal area, and a peripheral area with a grading scale of 0-3 and with a maximal total score of 9 for the nasal and temporal conjunctiva (overall the total score ranged from 0-18). Briefly, grade 0 reflects normal/healthy situation, whereas grade 3 reflects a severe damage in the considered sector.
    Time Frame At week 4

    Outcome Measure Data

    Analysis Population Description
    Full analysis set (FAS): The FAS consisted of all patients randomized who took at least 1 dose of IMP and who had at least 1 postbaseline efficacy measurement for the primary endpoint.
    Arm/Group Title rhNGF 20 μg/ml TID rhNGF 20 μg/ml BID + Vehicle OD Vehicle TID
    Arm/Group Description One drop of rhNGF 20 μg/ml will be instilled in both eyes three times daily (every 6-8 hours) rhNGF 20 μg/ml: one drop of rhNGF 20 μg/ml will be instilled in both eyes three times daily (every 6-8 hours) One drop of rhNGF 20 μg/ml will be instilled in both eyes two times daily (BID) plus one drop (40 μL) of vehicle will be instilled in both eyes once daily (OD) (every 6-8 hours) rhNGF 20 μg/ml + vehicle: one drop of rhNGF 20 μg/ml will be instilled in both eyes two times daily plus one drop (40 μL) of vehicle will be instilled in both eyes once daily (every 6-8 hours). rhNGF will be instilled in the morning and in the evening while the vehicle will be instilled in the afternoon. Vehicle eye one drop will be instilled in both eyes three times daily (every 6-8 hours) Vehicle: one drop of vehicle will be instilled in both eyes three times daily (every 6-8 hours)
    Measure Participants 81 82 84
    Count of Participants [Participants]
    2
    2.5%
    9
    11%
    3
    3.6%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.680
    Comments
    Method t-test, 2 sided
    Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.066
    Comments
    Method t-test, 2 sided
    Comments
    14. Secondary Outcome
    Title Number of Patients Who Experienced a Worsening in Symptom Scores (SANDE) and/or NEI Score ≥ 50% Assessed at Week 4 - Per Protocol Set
    Description The SANDE score is calculated by taking the square root of the product of the severity of symptoms score. The SANDE scale ranges from 0 to 100 with 100 being the maximal amount of dry eye symptoms and 0 being the minimal amount of dry eye symptoms. The NEI/Industry Workshop guidelines are used for grading the scale of corneal and conjunctival damage. The cornea is divided into five sectors (central, superior, inferior, nasal and temporal), each of which is scored on a scale of 0-3, with a maximal total corneal staining score of 15. Both nasally and temporally, the conjunctiva is divided into a superior paralimbal area, an inferior paralimbal area, and a peripheral area with a grading scale of 0-3 and with a maximal total score of 9 for the nasal and temporal conjunctiva (overall the total score ranged from 0-18). Briefly, grade 0 reflects normal/healthy situation, whereas grade 3 reflects a severe damage in the considered sector.
    Time Frame At week 4

    Outcome Measure Data

    Analysis Population Description
    Per protocol (PP) set: The PP set consisted of all patients in the FAS who fulfilled the study protocol requirements in terms of IMP intake and collection of primary efficacy data and had no major deviations that may have affected study results.
    Arm/Group Title rhNGF 20 μg/ml TID rhNGF 20 μg/ml BID + Vehicle OD Vehicle TID
    Arm/Group Description One drop of rhNGF 20 μg/ml will be instilled in both eyes three times daily (every 6-8 hours) rhNGF 20 μg/ml: one drop of rhNGF 20 μg/ml will be instilled in both eyes three times daily (every 6-8 hours) One drop of rhNGF 20 μg/ml will be instilled in both eyes two times daily (BID) plus one drop (40 μL) of vehicle will be instilled in both eyes once daily (OD) (every 6-8 hours) rhNGF 20 μg/ml + vehicle: one drop of rhNGF 20 μg/ml will be instilled in both eyes two times daily plus one drop (40 μL) of vehicle will be instilled in both eyes once daily (every 6-8 hours). rhNGF will be instilled in the morning and in the evening while the vehicle will be instilled in the afternoon. Vehicle eye one drop will be instilled in both eyes three times daily (every 6-8 hours) Vehicle: one drop of vehicle will be instilled in both eyes three times daily (every 6-8 hours)
    Measure Participants 72 71 80
    Count of Participants [Participants]
    0
    0%
    8
    9.8%
    3
    3.6%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.097
    Comments
    Method Chi-squared
    Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.076
    Comments
    Method Chi-squared
    Comments
    15. Secondary Outcome
    Title Change From Baseline in Quality of Life (Impact of Dry Eye on Everyday Life (IDEEL) Questionnaire vs Different Timepoints - Full Analysis Set
    Description IDEEL assesses quality of life, symptoms and treatment effects on patients with dry eye. The IDEEL contains 3 modules (Daily Activities, Treatment Satisfaction, and Symptom Bother) with a total of 57 questions. The Daily Activities Module is the quality of life instrument. It is comprised of 27 items. The IDEEL Treatment Satisfaction and Bother Module is divided into 2 sections, Treatment - In General and Treatment - Eye Drops. The Symptom Bother Module consists of 20 items in a single content domain, Symptom Bother. Scores for each dimensions ranged from 0 to 100. Higher scores for: dimension of the Dry Eye Impact on Daily Life module indicates less impact on daily activities; symptom-bother dimension indicates greater bother due to symptoms; satisfaction with Treatment Effectiveness dimension indicates greater satisfaction with treatment effectiveness; treatment-related bother/inconvenience indicates less treatment-related bother or inconvenience.
    Time Frame At weeks 4, 8, 12 and 16

    Outcome Measure Data

    Analysis Population Description
    Full analysis set (FAS): The FAS consisted of all patients randomized who took at least 1 dose of IMP and who had at least 1 postbaseline efficacy measurement for the primary endpoint.
    Arm/Group Title rhNGF 20 μg/ml TID rhNGF 20 μg/ml BID + Vehicle OD Vehicle TID
    Arm/Group Description One drop of rhNGF 20 μg/ml will be instilled in both eyes three times daily (every 6-8 hours) rhNGF 20 μg/ml: one drop of rhNGF 20 μg/ml will be instilled in both eyes three times daily (every 6-8 hours) One drop of rhNGF 20 μg/ml will be instilled in both eyes two times daily (BID) plus one drop (40 μL) of vehicle will be instilled in both eyes once daily (OD) (every 6-8 hours) rhNGF 20 μg/ml + vehicle: one drop of rhNGF 20 μg/ml will be instilled in both eyes two times daily plus one drop (40 μL) of vehicle will be instilled in both eyes once daily (every 6-8 hours). rhNGF will be instilled in the morning and in the evening while the vehicle will be instilled in the afternoon. Vehicle eye one drop will be instilled in both eyes three times daily (every 6-8 hours) Vehicle: one drop of vehicle will be instilled in both eyes three times daily (every 6-8 hours)
    Measure Participants 81 82 84
    Daily activity limitations - Chance from baseline to week 4
    16.5
    (20.71)
    19.5
    (17.55)
    13.1
    (20.60)
    Daily activity limitations - Chance from baseline to week 8
    16.8
    (23.49)
    14.8
    (18.07)
    11.2
    (17.54)
    Daily activity limitations - Chance from baseline to week 12
    15.7
    (21.10)
    15.5
    (20.01)
    11.1
    (17.45)
    Daily activity limitations - Chance from baseline to week 16
    14.2
    (20.05)
    14.4
    (21.23)
    9.4
    (16.74)
    Emotional well-being - change from baseline to week 4
    14.5
    (21.18)
    16.3
    (20.40)
    15.0
    (20.47)
    Emotional well-being - change from baseline to week 8
    16.2
    (21.33)
    13.4
    (18.64)
    12.7
    (17.69)
    Emotional well-being - change from baseline to week 12
    14.2
    (18.66)
    15.3
    (17.95)
    14.2
    (18.20)
    Emotional well-being - change from baseline to week 16
    16.0
    (18.54)
    15.5
    (19.17)
    13.5
    (20.22)
    work limitations - change from baseline to week 4
    16.3
    (27.13)
    20.6
    (24.29)
    17.4
    (24.09)
    work limitations - change from baseline to week 8
    18.0
    (24.94)
    18.3
    (19.00)
    17.0
    (22.52)
    work limitations - change from baseline to week 12
    16.4
    (22.39)
    20.9
    (22.05)
    17.8
    (22.35)
    work limitations - change from baseline to week 16
    16.3
    (20.75)
    20.9
    (20.83)
    16.0
    (21.63)
    Treatment satisfaction/happiness - change from baseline to week 4
    24.1
    (30.81)
    19.0
    (30.57)
    24.1
    (33.57)
    Treatment satisfaction/happiness - change from baseline to week 8
    28.8
    (28.56)
    19.1
    (26.90)
    13.3
    (30.69)
    Treatment satisfaction/happiness - change from baseline to week 12
    26.1
    (30.30)
    19.1
    (27.86)
    15.0
    (26.83)
    Treatment satisfaction/happiness - change from baseline to week 16
    26.1
    (26.62)
    23.5
    (29.29)
    12.7
    (27.03)
    treatment-related bother - change from baseline to week 4
    14.6
    (22.78)
    16.8
    (25.00)
    13.8
    (27.19)
    treatment-related bother - change from baseline to week 8
    10.6
    (20.61)
    6.5
    (26.56)
    4.8
    (26.59)
    treatment-related bother - change from baseline to week 12
    10.3
    (22.71)
    8.7
    (24.91)
    9.0
    (27.95)
    treatment-related bother - change from baseline to week 16
    10.8
    (20.65)
    8.1
    (23.88)
    10.0
    (27.14)
    Dry eye symptom bother - change from baseline to week 4
    -16.8
    (17.80)
    -17.7
    (16.54)
    -16.5
    (17.04)
    Dry eye symptom bother - change from baseline to week 8
    -21.2
    (19.56)
    -16.6
    (15.46)
    -13.5
    (15.01)
    Dry eye symptom bother - change from baseline to week 12
    -19.6
    (17.41)
    -18.2
    (17.30)
    -13.0
    (13.01)
    Dry eye symptom bother - change from baseline to week 16
    -19.9
    (15.62)
    -19.1
    (17.75)
    -11.1
    (14.46)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments Daily Activity Limitations - change from baseline to week 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.289
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 16.4
    Confidence Interval (2-Sided) 95%
    12.0 to 20.8
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments Daily Activity Limitations - change from baseline to week 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.032
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 19.7
    Confidence Interval (2-Sided) 95%
    15.4 to 24.0
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments Daily Activity Limitations - change to baseline to week 8
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.095
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 16.4
    Confidence Interval (2-Sided) 95%
    11.9 to 20.8
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments Daily Activity Limitations - change from baseline to week 8
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.282
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 14.5
    Confidence Interval (2-Sided) 95%
    10.1 to 18.8
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments Daily Activity Limitations - change from baseline to week 12
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.169
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 15.0
    Confidence Interval (2-Sided) 95%
    10.6 to 19.4
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments Daily Activity Limitations - change from baseline to week 12
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.129
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 15.4
    Confidence Interval (2-Sided) 95%
    11.1 to 19.7
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments Daily Activity Limitations - change from baseline to week 16
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.111
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 14.0
    Confidence Interval (2-Sided) 95%
    9.7 to 18.4
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 8
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments Daily Activity Limitations - change from baseline to week 16
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.107
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 14.0
    Confidence Interval (2-Sided) 95%
    9.7 to 18.3
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 9
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments Emotional Well-Being - change from baseline to week 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.827
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 14.3
    Confidence Interval (2-Sided) 95%
    9.7 to 18.9
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 10
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments Emotional Well-Being - change from baseline to week 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.688
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 16.3
    Confidence Interval (2-Sided) 95%
    11.8 to 20.8
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 11
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments Emotional Well-Being - change from baseline to week 8
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.324
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 15.7
    Confidence Interval (2-Sided) 95%
    11.4 to 20.0
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 12
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments Emotional Well-Being - change from baseline to week 8
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.949
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 12.9
    Confidence Interval (2-Sided) 95%
    8.7 to 17.1
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 13
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments Emotional Well-Being - change from baseline to week 12
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.927
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 15.7
    Confidence Interval (2-Sided) 95%
    11.4 to 20.1
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 14
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments Emotional Well-Being - change from baseline to week 12
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.776
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 14.8
    Confidence Interval (2-Sided) 95%
    10.8 to 18.8
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 15
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments Emotional Well-Being - change from baseline to week 16
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.418
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 15.7
    Confidence Interval (2-Sided) 95%
    11.4 to 20.1
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 16
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments Emotional Well-Being - change from baseline to week 16
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.613
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 14.8
    Confidence Interval (2-Sided) 95%
    10.6 to 19.0
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 17
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments Work Limitations - change from baseline to week 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.721
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 15.8
    Confidence Interval (2-Sided) 95%
    8.3 to 23.2
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 18
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments Work Limitations - change from baseline to week 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.558
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 20.6
    Confidence Interval (2-Sided) 95%
    13.1 to 28.0
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 19
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments Work Limitations - change from baseline to week 8
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.809
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 18.4
    Confidence Interval (2-Sided) 95%
    11.5 to 25.3
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 20
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments Work Limitations - change from baseline to week 8
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.651
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 19.4
    Confidence Interval (2-Sided) 95%
    12.4 to 26.4
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 21
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments Work Limitations - change from baseline to week 12
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.769
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 16.4
    Confidence Interval (2-Sided) 95%
    9.5 to 23.3
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 22
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments Work Limitations - change from baseline to week 12
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.454
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 21.3
    Confidence Interval (2-Sided) 95%
    14.3 to 28.3
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 23
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments Work Limitations - change from baseline to week 16
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.564
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 18.3
    Confidence Interval (2-Sided) 95%
    11.6 to 25.0
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 24
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments Work Limitations - change from baseline to week 16
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.250
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 21.0
    Confidence Interval (2-Sided) 95%
    14.1 to 27.8
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 25
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments Treatment Satisfaction - change from baseline to week 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.853
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 23.9
    Confidence Interval (2-Sided) 95%
    15.6 to 32.2
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 26
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments Treatment Satisfaction - change from baseline to week 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.393
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 20.0
    Confidence Interval (2-Sided) 95%
    11.9 to 28.0
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 27
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments Treatment Satisfaction - change from baseline to week 8
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.010
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 27.9
    Confidence Interval (2-Sided) 95%
    20.2 to 35.6
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 28
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments Treatment Satisfaction - change from baseline to week 8
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.395
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 18.3
    Confidence Interval (2-Sided) 95%
    11.1 to 25.4
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 29
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments Treatment Satisfaction - change from baseline to week 12
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.068
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 24.8
    Confidence Interval (2-Sided) 95%
    17.1 to 32.4
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 30
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments Treatment Satisfaction - change from baseline to week 12
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.400
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 19.3
    Confidence Interval (2-Sided) 95%
    12.2 to 26.4
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 31
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments Treatment Satisfaction - change from baseline to week 16
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.021
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 25.5
    Confidence Interval (2-Sided) 95%
    18.1 to 33.0
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 32
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments Treatment Satisfaction - change from baseline to week 16
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.056
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 23.1
    Confidence Interval (2-Sided) 95%
    16.1 to 30.0
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 33
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments Treatment-Related Bother - change from baseline to week 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.981
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 14.2
    Confidence Interval (2-Sided) 95%
    7.6 to 20.7
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 34
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments Treatment-Related Bother - change from baseline to week 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.525
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 17.0
    Confidence Interval (2-Sided) 95%
    11.1 to 22.9
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 35
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments Treatment-Related Bother - change from baseline to week 8
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.356
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 9.5
    Confidence Interval (2-Sided) 95%
    2.9 to 16.0
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 36
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments Treatment-Related Bother - change from baseline to week 8
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.771
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 6.5
    Confidence Interval (2-Sided) 95%
    0.7 to 12.4
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 37
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments Treatment-Related Bother - change from baseline to week 12
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.926
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 8.7
    Confidence Interval (2-Sided) 95%
    2.0 to 15.5
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 38
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments Treatment-Related Bother - change from baseline to week 12
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.778
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 7.9
    Confidence Interval (2-Sided) 95%
    1.9 to 13.9
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 39
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments Treatment-Related Bother - change from baseline to week 16
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.984
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 10.0
    Confidence Interval (2-Sided) %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 40
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments Treatment-Related Bother - change from baseline to week 16
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.514
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 7.4
    Confidence Interval (2-Sided) 95%
    1.6 to 13.1
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 41
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments Symptom Bother - change from baseline to week 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.985
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value -16.6
    Confidence Interval (2-Sided) 95%
    -20.4 to -12.8
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 42
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments Symptom Bother - change from baseline to week 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.646
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value -17.8
    Confidence Interval (2-Sided) 95%
    -21.5 to -14.0
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 43
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments Symptom Bother - change from baseline to week 8
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.007
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value -20.7
    Confidence Interval (2-Sided) 95%
    -24.5 to -16.9
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 44
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments Symptom Bother - change from baseline to week 8
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.305
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value -16.2
    Confidence Interval (2-Sided) 95%
    -19.9 to -12.5
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 45
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments Symptom Bother - change from baseline to week 12
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.015
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value -19.0
    Confidence Interval (2-Sided) 95%
    -22.7 to -15.4
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 46
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments Symptom Bother - change from baseline to week 12
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.039
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value -18.0
    Confidence Interval (2-Sided) 95%
    -21.5 to -14.4
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 47
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.001
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value -19.7
    Confidence Interval (2-Sided) 95%
    -23.3 to -16.0
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 48
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments Symptom Bother - change from baseline to week 16
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.002
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value -18.9
    Confidence Interval (2-Sided) 95%
    -22.4 to -15.3
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    16. Secondary Outcome
    Title Change From Baseline in Quality of Life (Impact of Dry Eye on Everyday Life (IDEEL) Questionnaire vs Different Timepoints - Per Protocol Set
    Description IDEEL assesses quality of life, symptoms and treatment effects on patients with dry eye. The IDEEL contains 3 modules (Daily Activities, Treatment Satisfaction, and Symptom Bother) with a total of 57 questions. The Daily Activities Module is the quality of life instrument. It is comprised of 27 items. The IDEEL Treatment Satisfaction and Bother Module is divided into 2 sections, Treatment - In General and Treatment - Eye Drops. The Symptom Bother Module consists of 20 items in a single content domain, Symptom Bother. Scores for each dimensions ranged from 0 to 100. Higher scores for: dimension of the Dry Eye Impact on Daily Life module indicates less impact on daily activities; symptom-bother dimension indicates greater bother due to symptoms; satisfaction with Treatment Effectiveness dimension indicates greater satisfaction with treatment effectiveness; treatment-related bother/inconvenience indicates less treatment-related bother or inconvenience.
    Time Frame At weeks 4, 8, 12 and 16

    Outcome Measure Data

    Analysis Population Description
    Per protocol (PP) set: The PP set consisted of all patients in the FAS who fulfilled the study protocol requirements in terms of IMP intake and collection of primary efficacy data and had no major deviations that may have affected study results.
    Arm/Group Title rhNGF 20 μg/ml TID rhNGF 20 μg/ml BID + Vehicle OD Vehicle TID
    Arm/Group Description One drop of rhNGF 20 μg/ml will be instilled in both eyes three times daily (every 6-8 hours) rhNGF 20 μg/ml: one drop of rhNGF 20 μg/ml will be instilled in both eyes three times daily (every 6-8 hours) One drop of rhNGF 20 μg/ml will be instilled in both eyes two times daily (BID) plus one drop (40 μL) of vehicle will be instilled in both eyes once daily (OD) (every 6-8 hours) rhNGF 20 μg/ml + vehicle: one drop of rhNGF 20 μg/ml will be instilled in both eyes two times daily plus one drop (40 μL) of vehicle will be instilled in both eyes once daily (every 6-8 hours). rhNGF will be instilled in the morning and in the evening while the vehicle will be instilled in the afternoon. Vehicle eye one drop will be instilled in both eyes three times daily (every 6-8 hours) Vehicle: one drop of vehicle will be instilled in both eyes three times daily (every 6-8 hours)
    Measure Participants 72 71 80
    Daily activity limitations - Change from baseline to week 4
    16.8
    (21.20)
    19.7
    (17.58)
    13.0
    (20.63)
    Daily activity limitations - Change from baseline to week 8
    17.1
    (23.93)
    15.3
    (16.85)
    11.5
    (17.47)
    Daily activity limitations - Change from baseline to week 12
    17.0
    (20.30)
    16.5
    (18.45)
    11.2
    (17.64)
    Daily activity limitations - Change from baseline to week 16
    13.9
    (19.33)
    15.8
    (19.74)
    9.4
    (16.94)
    Emotional well-being - change from baseline to week 4
    15.2
    (21.73)
    17.3
    (20.33)
    15.8
    (20.60)
    Emotional well-being - change from baseline to week 8
    16.9
    (21.70)
    13.9
    (18.34)
    13.2
    (17.55)
    Emotional well-being - change from baseline to week 12
    15.1
    (18.58)
    16.4
    (16.87)
    14.7
    (18.14)
    Emotional well-being - change from baseline to week 16
    16.8
    (18.48)
    16.6
    (18.59)
    14.2
    (20.11)
    work limitations - change from baseline to week 4
    16.0
    (27.48)
    21.3
    (24.83)
    18.4
    (24.23)
    work limitations - change from baseline to week 8
    17.4
    (25.13)
    18.3
    (19.43)
    17.9
    (22.29)
    work limitations - change from baseline to week 12
    15.0
    (21.67)
    21.9
    (21.82)
    18.6
    (22.14)
    work limitations - change from baseline to week 16
    15.4
    (19.43)
    21.9
    (20.93)
    16.7
    (21.80)
    Treatment satisfaction/happiness - change from baseline to week 4
    25.4
    (31.05)
    19.6
    (31.26)
    25.2
    (33.81)
    Treatment satisfaction/happiness - change from baseline to week 8
    30.1
    (28.47)
    21.0
    (27.85)
    13.9
    (30.66)
    Treatment satisfaction/happiness - change from baseline to week 12
    25.8
    (31.16)
    21.6
    (27.82)
    15.5
    (26.81)
    Treatment satisfaction/happiness - change from baseline to week 16
    26.0
    (27.60)
    24.3
    (28.26)
    13.2
    (27.18)
    treatment-related bother - change from baseline to week 4
    15.7
    (22.66)
    15.3
    (23.39)
    14.4
    (27.71)
    treatment-related bother - change from baseline to week 8
    11.6
    (20.73)
    6.9
    (25.46)
    4.6
    (26.78)
    treatment-related bother - change from baseline to week 12
    9.9
    (22.83)
    10.0
    (23.05)
    8.7
    (28.26)
    treatment-related bother - change from baseline to week 16
    11.4
    (20.90)
    9.5
    (21.62)
    9.8
    (27.51)
    Dry eye symptom bother - change from baseline to week 4
    -17.3
    (17.19)
    -18.7
    (16.64)
    -17.2
    (17.10)
    Dry eye symptom bother - change from baseline to week 8
    -21.5
    (18.88)
    -17.6
    (15.40)
    -13.9
    (14.97)
    Dry eye symptom bother - change from baseline to week 12
    -19.6
    (17.41)
    -19.7
    (17.16)
    -13.2
    (13.18)
    Dry eye symptom bother - change from baseline to week 16
    -20.6
    (15.21)
    -20.7
    (17.66)
    -11.3
    (14.61)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments Daily Activity Limitations - change from baseline to week 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.241
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 16.8
    Confidence Interval (2-Sided) 95%
    12.2 to 21.4
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments Daily Activity Limitations - change from baseline to week 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.040
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 19.7
    Confidence Interval (2-Sided) 95%
    15.1 to 24.4
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments Daily Activity Limitations - change from baseline to week 8
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.097
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 16.8
    Confidence Interval (2-Sided) 95%
    12.3 to 21.4
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments Daily Activity Limitations - change from baseline to week 8
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.238
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 15.3
    Confidence Interval (2-Sided) 95%
    10.7 to 19.9
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments Daily Activity Limitations - change from baseline to week 12
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.070
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 16.5
    Confidence Interval (2-Sided) 95%
    12.0 to 20.9
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments Daily Activity Limitations - change from baseline to week 12
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.058
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 16.7
    Confidence Interval (2-Sided) 95%
    12.3 to 21.1
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, rhNGF 20 μg/ml BID + Vehicle OD
    Comments Daily Activity Limitations - change from baseline to week 16
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.128
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 13.7
    Confidence Interval (2-Sided) 95%
    9.3 to 18.1
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 8
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments Daily Activity Limitations - change from baseline to week 16
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.024
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 16.0
    Confidence Interval (2-Sided) 95%
    11.6 to 20.3
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 9
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments Emotional Well-Being - change from baseline to week 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.865
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 15.2
    Confidence Interval (2-Sided) 95%
    10.4 to 20.1
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 10
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments Emotional Well-Being - change from baseline to week 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.662
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 17.3
    Confidence Interval (2-Sided) 95%
    12.4 to 22.2
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 11
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, rhNGF 20 μg/ml BID + Vehicle OD
    Comments Emotional Well-Being - change from baseline to week 8
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.266
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 16.7
    Confidence Interval (2-Sided) 95%
    12.2 to 21.1
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 12
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments Emotional Well-Being - change from baseline to week 8
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.824
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 13.9
    Confidence Interval (2-Sided) 95%
    9.4 to 18.3
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 13
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, rhNGF 20 μg/ml BID + Vehicle OD
    Comments Emotional Well-Being - change from baseline to week 12
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.883
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 14.8
    Confidence Interval (2-Sided) 95%
    10.6 to 19.0
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 14
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments Emotional Well-Being - change from baseline to week 12
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.516
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 16.3
    Confidence Interval (2-Sided) 95%
    12.1 to 20.4
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 15
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, rhNGF 20 μg/ml BID + Vehicle OD
    Comments Emotional Well-Being - change from baseline to week 16
    Type of Statistical Test Superiority
    Comments Emotional Well-Being - change from baseline to week 16
    Statistical Test of Hypothesis p-Value 0.407
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 16.5
    Confidence Interval (2-Sided) 95%
    12.1 to 21.0
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 16
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments Emotional Well-Being - change from baseline to week 16
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.422
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 16.4
    Confidence Interval (2-Sided) 95%
    12.0 to 20.9
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 17
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, rhNGF 20 μg/ml BID + Vehicle OD
    Comments Work Limitations - change from baseline to week 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.615
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 15.9
    Confidence Interval (2-Sided) 95%
    8.1 to 23.8
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 18
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments Work Limitations - change from baseline to week 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.626
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 21.3
    Confidence Interval (2-Sided) 95%
    13.3 to 29.2
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 19
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, rhNGF 20 μg/ml BID + Vehicle OD
    Comments Work Limitations - change from baseline to week 8
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.968
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 18.3
    Confidence Interval (2-Sided) 95%
    11.1 to 25.6
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 20
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.689
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 20.1
    Confidence Interval (2-Sided) 95%
    12.8 to 27.4
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 21
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, rhNGF 20 μg/ml BID + Vehicle OD
    Comments Work Limitations - change from baseline to week 12
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.528
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 15.6
    Confidence Interval (2-Sided) 95%
    8.5 to 22.7
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 22
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments Work Limitations - change from baseline to week 12
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.368
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 23.0
    Confidence Interval (2-Sided) 95%
    15.8 to 30.1
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 23
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, rhNGF 20 μg/ml BID + Vehicle OD
    Comments Work Limitations - change from baseline to week 16
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.764
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 17.7
    Confidence Interval (2-Sided) 95%
    10.7 to 24.7
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 24
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments Work Limitations - change from baseline to week 16
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.184
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 22.6
    Confidence Interval (2-Sided) 95%
    15.5 to 29.6
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 25
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments Treatment Satisfaction - change from baseline to week 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.909
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 25.4
    Confidence Interval (2-Sided) 95%
    16.5 to 34.2
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 26
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments Treatment Satisfaction - change from baseline to week 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.428
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 21.1
    Confidence Interval (2-Sided) 95%
    12.2 to 30.0
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 27
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments Treatment Satisfaction - change from baseline to week 8
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.008
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 29.8
    Confidence Interval (2-Sided) 95%
    21.6 to 37.9
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 28
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments Treatment Satisfaction - change from baseline to week 8
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.222
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 21.3
    Confidence Interval (2-Sided) 95%
    13.5 to 29.2
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 29
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, rhNGF 20 μg/ml BID + Vehicle OD
    Comments Treatment Satisfaction - change from baseline to week 12
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.082
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 25.3
    Confidence Interval (2-Sided) 95%
    17.2 to 33.4
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 30
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments Treatment Satisfaction - change from baseline to week 12
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.154
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 23.3
    Confidence Interval (2-Sided) 95%
    15.6 to 31.1
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 31
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments Treatment Satisfaction - change from baseline to week 16
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.030
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 25.8
    Confidence Interval (2-Sided) 95%
    18.0 to 33.6
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 32
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments Treatment Satisfaction - change from baseline to week 16
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.046
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 24.6
    Confidence Interval (2-Sided) 95%
    17.1 to 32.1
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 33
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments Treatment-Related Bother - change from baseline to week 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.861
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 15.4
    Confidence Interval (2-Sided) 95%
    8.6 to 22.2
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 34
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments Treatment-Related Bother - change from baseline to week 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.865
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 15.3
    Confidence Interval (2-Sided) 95%
    9.0 to 21.7
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 35
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, rhNGF 20 μg/ml BID + Vehicle OD
    Comments Treatment-Related Bother - change from baseline to week 8
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.278
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 10.5
    Confidence Interval (2-Sided) 95%
    3.6 to 17.3
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 36
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments Treatment-Related Bother - change from baseline to week 8
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.689
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 7.2
    Confidence Interval (2-Sided) 95%
    0.9 to 13.5
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 37
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, rhNGF 20 μg/ml BID + Vehicle OD
    Comments Treatment-Related Bother - change from baseline to week 12
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.993
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 9.1
    Confidence Interval (2-Sided) 95%
    2.1 to 16.2
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 38
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments Treatment-Related Bother - change from baseline to week 12
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.989
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 9.2
    Confidence Interval (2-Sided) 95%
    2.8 to 15.7
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 39
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, rhNGF 20 μg/ml BID + Vehicle OD
    Comments Treatment-Related Bother - change from baseline to week 16
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.976
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 10.4
    Confidence Interval (2-Sided) 95%
    3.7 to 17.0
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 40
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments Treatment-Related Bother - change from baseline to week 16
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.778
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 9.0
    Confidence Interval (2-Sided) 95%
    2.9 to 15.1
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 41
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, rhNGF 20 μg/ml BID + Vehicle OD
    Comments Symptom Bother - change from baseline to week 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.964
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value -17.3
    Confidence Interval (2-Sided) 95%
    -21.2 to -13.3
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 42
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments Symptom Bother - change from baseline to week 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.581
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value -18.7
    Confidence Interval (2-Sided) 95%
    -22.7 to -14.7
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 43
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, rhNGF 20 μg/ml BID + Vehicle OD
    Comments Symptom Bother - change from baseline to week 8
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.006
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value -21.4
    Confidence Interval (2-Sided) 95%
    -25.2 to -17.5
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 44
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments Symptom Bother - change from baseline to week 8
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.175
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value -17.6
    Confidence Interval (2-Sided) 95%
    -21.4 to -13.7
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 45
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, rhNGF 20 μg/ml BID + Vehicle OD
    Comments Symptom Bother - change from baseline to week 12
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.016
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value -19.4
    Confidence Interval (2-Sided) 95%
    -23.1 to -15.6
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 46
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments Symptom Bother - change from baseline to week 12
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.010
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value -19.8
    Confidence Interval (2-Sided) 95%
    -23.5 to -16.1
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 47
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, rhNGF 20 μg/ml BID + Vehicle OD
    Comments Symptom Bother - change from baseline to week 16
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.000
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value -20.5
    Confidence Interval (2-Sided) 95%
    -24.3 to -16.8
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 48
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments Symptom Bother - change from baseline to week 16
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.000
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value -20.8
    Confidence Interval (2-Sided) 95%
    -24.6 to -17.1
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    17. Secondary Outcome
    Title Patient Global Impression of Change (PGIC) - Full Analysis Set
    Description PGIC is a commonly used method of assessing clinically important change. With PGIC the qualitative assessment of meaningful change is determined by the patient on 7-items using a 0 (very much improved) to 10 (very much worse) scale.
    Time Frame At baseline and weeks 4, 8, 12 and 16

    Outcome Measure Data

    Analysis Population Description
    Full analysis set (FAS): The FAS consisted of all patients randomized who took at least 1 dose of IMP and who had at least 1 postbaseline efficacy measurement for the primary endpoint.
    Arm/Group Title rhNGF 20 μg/ml TID rhNGF 20 μg/ml BID + Vehicle OD Vehicle TID
    Arm/Group Description One drop of rhNGF 20 μg/ml will be instilled in both eyes three times daily (every 6-8 hours) rhNGF 20 μg/ml: one drop of rhNGF 20 μg/ml will be instilled in both eyes three times daily (every 6-8 hours) One drop of rhNGF 20 μg/ml will be instilled in both eyes two times daily (BID) plus one drop (40 μL) of vehicle will be instilled in both eyes once daily (OD) (every 6-8 hours) rhNGF 20 μg/ml + vehicle: one drop of rhNGF 20 μg/ml will be instilled in both eyes two times daily plus one drop (40 μL) of vehicle will be instilled in both eyes once daily (every 6-8 hours). rhNGF will be instilled in the morning and in the evening while the vehicle will be instilled in the afternoon. Vehicle eye one drop will be instilled in both eyes three times daily (every 6-8 hours) Vehicle: one drop of vehicle will be instilled in both eyes three times daily (every 6-8 hours)
    Measure Participants 81 82 84
    week 4 - Very Much Improved
    11
    13.6%
    2
    2.4%
    4
    4.8%
    week 4 - Much Improved
    18
    22.2%
    15
    18.3%
    20
    23.8%
    week 4 - Minimally improved
    18
    22.2%
    21
    25.6%
    20
    23.8%
    week 4 - no change
    24
    29.6%
    38
    46.3%
    38
    45.2%
    week 4 - minimally worse
    6
    7.4%
    4
    4.9%
    2
    2.4%
    week 4 - much worse
    1
    1.2%
    1
    1.2%
    0
    0%
    week 4 - very much worse
    0
    0%
    0
    0%
    0
    0%
    week 8 - Very much improved
    9
    11.1%
    3
    3.7%
    1
    1.2%
    week 8 - much improved
    23
    28.4%
    11
    13.4%
    16
    19%
    week 8 - minimally improved
    19
    23.5%
    21
    25.6%
    17
    20.2%
    week 8 - no change
    21
    25.9%
    37
    45.1%
    46
    54.8%
    week 8 - minimally worse
    1
    1.2%
    4
    4.9%
    2
    2.4%
    week 8 - much worse
    0
    0%
    1
    1.2%
    2
    2.4%
    week 8 - very much worse
    1
    1.2%
    1
    1.2%
    0
    0%
    week 12 - very much improved
    11
    13.6%
    3
    3.7%
    4
    4.8%
    week 12 - much improved
    16
    19.8%
    10
    12.2%
    12
    14.3%
    week 12 - minimally improved
    22
    27.2%
    24
    29.3%
    24
    28.6%
    week 12 - no change
    15
    18.5%
    36
    43.9%
    40
    47.6%
    week 12 - minimally worse
    5
    6.2%
    1
    1.2%
    0
    0%
    week 12 - much worse
    2
    2.5%
    2
    2.4%
    2
    2.4%
    week 12 - very much worse
    2
    2.5%
    1
    1.2%
    0
    0%
    week 16 - very much improved
    7
    8.6%
    3
    3.7%
    6
    7.1%
    week 16 - much improved
    24
    29.6%
    19
    23.2%
    16
    19%
    week 16 - minimally improved
    22
    27.2%
    20
    24.4%
    19
    22.6%
    week 16 - no change
    19
    23.5%
    33
    40.2%
    36
    42.9%
    week 16 - minimally worse
    2
    2.5%
    2
    2.4%
    5
    6%
    week 16 - much worse
    1
    1.2%
    0
    0%
    0
    0%
    week 16 - very much worse
    0
    0%
    1
    1.2%
    0
    0%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments at week 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.302
    Comments
    Method Wilcoxon (Mann-Whitney)
    Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments at week 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.224
    Comments
    Method Wilcoxon (Mann-Whitney)
    Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments at week 8 (FUP)
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.000
    Comments
    Method Wilcoxon (Mann-Whitney)
    Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments at week 8 (FUP)
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.885
    Comments
    Method Wilcoxon (Mann-Whitney)
    Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments At week 12 (FUP)
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.035
    Comments
    Method Wilcoxon (Mann-Whitney)
    Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments At week 12 (FUP)
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.698
    Comments
    Method Wilcoxon (Mann-Whitney)
    Comments
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments At week 16 (FUP)
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.016
    Comments
    Method Wilcoxon (Mann-Whitney)
    Comments
    Statistical Analysis 8
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments At week 16 (FUP)
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.706
    Comments
    Method Wilcoxon (Mann-Whitney)
    Comments
    18. Secondary Outcome
    Title Patient Global Impression of Change (PGIC) - Per Protocol Set
    Description PGIC is a commonly used method of assessing clinically important change. With PGIC the qualitative assessment of meaningful change is determined by the patient on 7-items using a 0 (very much improved) to 10 (very much worse) scale.
    Time Frame At weeks 4, 8, 12 and 16

    Outcome Measure Data

    Analysis Population Description
    Per protocol (PP) set: The PP set consisted of all patients in the FAS who fulfilled the study protocol requirements in terms of IMP intake and collection of primary efficacy data and had no major deviations that may have affected study results.
    Arm/Group Title rhNGF 20 μg/ml TID rhNGF 20 μg/ml BID + Vehicle OD Vehicle TID
    Arm/Group Description One drop of rhNGF 20 μg/ml will be instilled in both eyes three times daily (every 6-8 hours) rhNGF 20 μg/ml: one drop of rhNGF 20 μg/ml will be instilled in both eyes three times daily (every 6-8 hours) One drop of rhNGF 20 μg/ml will be instilled in both eyes two times daily (BID) plus one drop (40 μL) of vehicle will be instilled in both eyes once daily (OD) (every 6-8 hours) rhNGF 20 μg/ml + vehicle: one drop of rhNGF 20 μg/ml will be instilled in both eyes two times daily plus one drop (40 μL) of vehicle will be instilled in both eyes once daily (every 6-8 hours). rhNGF will be instilled in the morning and in the evening while the vehicle will be instilled in the afternoon. Vehicle eye one drop will be instilled in both eyes three times daily (every 6-8 hours) Vehicle: one drop of vehicle will be instilled in both eyes three times daily (every 6-8 hours)
    Measure Participants 72 71 80
    week 4 - Very Much Improved
    10
    12.3%
    2
    2.4%
    4
    4.8%
    week 4 - Much Improved
    18
    22.2%
    12
    14.6%
    18
    21.4%
    week 4 - Minimally improved
    17
    21%
    19
    23.2%
    20
    23.8%
    week 4 - no change
    20
    24.7%
    34
    41.5%
    36
    42.9%
    week 4 - minimally worse
    6
    7.4%
    4
    4.9%
    2
    2.4%
    week 4 - much worse
    1
    1.2%
    0
    0%
    0
    0%
    week 4 - very much worse
    0
    0%
    0
    0%
    0
    0%
    week 8 - Very much improved
    9
    11.1%
    3
    3.7%
    1
    1.2%
    week 8 - much improved
    21
    25.9%
    9
    11%
    15
    17.9%
    week 8 - minimally improved
    18
    22.2%
    21
    25.6%
    17
    20.2%
    week 8 - no change
    20
    24.7%
    34
    41.5%
    43
    51.2%
    week 8 - minimally worse
    1
    1.2%
    3
    3.7%
    2
    2.4%
    week 8 - much worse
    0
    0%
    1
    1.2%
    2
    2.4%
    week 8 - very much worse
    0
    0%
    0
    0%
    0
    0%
    week 12 - very much improved
    11
    13.6%
    3
    3.7%
    4
    4.8%
    week 12 - much improved
    13
    16%
    9
    11%
    11
    13.1%
    week 12 - minimally improved
    21
    25.9%
    23
    28%
    23
    27.4%
    week 12 - no change
    15
    18.5%
    33
    40.2%
    38
    45.2%
    week 12 - minimally worse
    5
    6.2%
    1
    1.2%
    0
    0%
    week 12 - much worse
    2
    2.5%
    1
    1.2%
    2
    2.4%
    week 12 - very much worse
    1
    1.2%
    0
    0%
    0
    0%
    week 16 - very much improved
    7
    8.6%
    3
    3.7%
    6
    7.1%
    week 16 - much improved
    22
    27.2%
    18
    22%
    15
    17.9%
    week 16 - minimally improved
    19
    23.5%
    17
    20.7%
    18
    21.4%
    week 16 - no change
    19
    23.5%
    30
    36.6%
    34
    40.5%
    week 16 - minimally worse
    2
    2.5%
    2
    2.4%
    5
    6%
    week 16 - much worse
    0
    0%
    0
    0%
    0
    0%
    week 16 - very much worse
    0
    0%
    0
    0%
    0
    0%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments at week 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.210
    Comments
    Method Wilcoxon (Mann-Whitney)
    Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments at weeek 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.260
    Comments
    Method Wilcoxon (Mann-Whitney)
    Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments At week 8 (FUP)
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.000
    Comments
    Method Wilcoxon (Mann-Whitney)
    Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments at week 8 (FUP)
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.734
    Comments
    Method Wilcoxon (Mann-Whitney)
    Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments at week 12 (FUP)
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.050
    Comments
    Method Wilcoxon (Mann-Whitney)
    Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments at week 12 (FUP)
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.985
    Comments
    Method Wilcoxon (Mann-Whitney)
    Comments
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments at week 16 (FUP)
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.018
    Comments
    Method Wilcoxon (Mann-Whitney)
    Comments
    Statistical Analysis 8
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments at week 16 (FUP)
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.580
    Comments
    Method Wilcoxon (Mann-Whitney)
    Comments
    19. Secondary Outcome
    Title Change From Baseline in EQ-5D-3L Questionnaire to Different Timepoints - Full Analysis Set
    Description EQ-5D is a standardised measure of health status. - The EQ-5D 3 level version (EQ-5D-3L) consists of the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS) which are summed up. The EQ-5D-3L descriptive system comprises 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. This scale ranges from 5 (best case) to 15 (worst case). Each dimension has 3 levels: no problems, some problems, extreme problems (labelled 1-3). The respondent must indicate his/her health state by ticking (or placing a cross) in the box against the most appropriate statement in each of the 5 dimensions. - The EQ VAS records the respondent's self-rated health on a vertical, visual analogue scale where the endpoints are labelled 'Best imaginable health state' and 'Worst imaginable health state'. This is a quantitative measure of health outcome, judged by each respondent. Both for total and partial scores, the higher the score, the worse is the outcome.
    Time Frame At weeks 4, 8, 12 and 16

    Outcome Measure Data

    Analysis Population Description
    Full analysis set (FAS): The FAS consisted of all patients randomized who took at least 1 dose of IMP and who had at least 1 postbaseline efficacy measurement for the primary endpoint.
    Arm/Group Title rhNGF 20 μg/ml TID rhNGF 20 μg/ml BID + Vehicle OD Vehicle TID
    Arm/Group Description One drop of rhNGF 20 μg/ml will be instilled in both eyes three times daily (every 6-8 hours) rhNGF 20 μg/ml: one drop of rhNGF 20 μg/ml will be instilled in both eyes three times daily (every 6-8 hours) One drop of rhNGF 20 μg/ml will be instilled in both eyes two times daily (BID) plus one drop (40 μL) of vehicle will be instilled in both eyes once daily (OD) (every 6-8 hours) rhNGF 20 μg/ml + vehicle: one drop of rhNGF 20 μg/ml will be instilled in both eyes two times daily plus one drop (40 μL) of vehicle will be instilled in both eyes once daily (every 6-8 hours). rhNGF will be instilled in the morning and in the evening while the vehicle will be instilled in the afternoon. Vehicle eye one drop will be instilled in both eyes three times daily (every 6-8 hours) Vehicle: one drop of vehicle will be instilled in both eyes three times daily (every 6-8 hours)
    Measure Participants 81 82 84
    week 4
    1.2
    (9.91)
    3.8
    (10.28)
    2.8
    (8.86)
    week 8
    2.7
    (10.41)
    2.4
    (8.92)
    2.1
    (8.86)
    week 12
    3.0
    (10.10)
    3.0
    (7.8)
    3.0
    (8.59)
    week 16
    3.0
    (13.04)
    4.8
    (11.92)
    2.0
    (11.71)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments statistical analysis at week 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.282
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 1.2
    Confidence Interval (2-Sided) 95%
    -1.0 to 3.3
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments statistical analysis at week 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.497
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 3.9
    Confidence Interval (2-Sided) 95%
    1.7 to 6.0
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments statistical analysis at week 8
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.734
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 2.6
    Confidence Interval (2-Sided) 95%
    0.5 to 4.8
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments statistical analysis at week 8
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.963
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 2.2
    Confidence Interval (2-Sided) 95%
    0.1 to 4.3
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments statistical analysis at week 12
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.854
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 2.7
    Confidence Interval (2-Sided) 95%
    0.7 to 4.8
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments statistical analysis at week 12
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.881
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 2.8
    Confidence Interval (2-Sided) 95%
    0.8 to 4.8
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments statistical analysis at week 16
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.632
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 3.0
    Confidence Interval (2-Sided) 95%
    0.3 to 5.7
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 8
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments statistical analysis at week 16
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.220
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 4.4
    Confidence Interval (2-Sided) 95%
    1.7 to 7.0
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    20. Secondary Outcome
    Title Change From Baseline in EQ-5D-3L Questionnaire to Different Timepoints - Per Protocol Set
    Description EQ-5D is a standardised measure of health status. - The EQ-5D 3 level version (EQ-5D-3L) consists of the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS) which are summed up. The EQ-5D-3L descriptive system comprises 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. This scale ranges from 5 (best case) to 15 (worst case). Each dimension has 3 levels: no problems, some problems, extreme problems (labelled 1-3). The respondent must indicate his/her health state by ticking (or placing a cross) in the box against the most appropriate statement in each of the 5 dimensions. - The EQ VAS records the respondent's self-rated health on a vertical, visual analogue scale where the endpoints are labelled 'Best imaginable health state' and 'Worst imaginable health state'. This is a quantitative measure of health outcome, judged by each respondent. Both for total and partial scores, the higher the score, the worse is the outcome.
    Time Frame Aat baseline and weeks 4, 8, 12 and 16

    Outcome Measure Data

    Analysis Population Description
    Per protocol (PP) set: The PP set consisted of all patients in the FAS who fulfilled the study protocol requirements in terms of IMP intake and collection of primary efficacy data and had no major deviations that may have affected study results.
    Arm/Group Title rhNGF 20 μg/ml TID rhNGF 20 μg/ml BID + Vehicle OD Vehicle TID
    Arm/Group Description One drop of rhNGF 20 μg/ml will be instilled in both eyes three times daily (every 6-8 hours) rhNGF 20 μg/ml: one drop of rhNGF 20 μg/ml will be instilled in both eyes three times daily (every 6-8 hours) One drop of rhNGF 20 μg/ml will be instilled in both eyes two times daily (BID) plus one drop (40 μL) of vehicle will be instilled in both eyes once daily (OD) (every 6-8 hours) rhNGF 20 μg/ml + vehicle: one drop of rhNGF 20 μg/ml will be instilled in both eyes two times daily plus one drop (40 μL) of vehicle will be instilled in both eyes once daily (every 6-8 hours). rhNGF will be instilled in the morning and in the evening while the vehicle will be instilled in the afternoon. Vehicle eye one drop will be instilled in both eyes three times daily (every 6-8 hours) Vehicle: one drop of vehicle will be instilled in both eyes three times daily (every 6-8 hours)
    Measure Participants 72 71 80
    week 4
    1.2
    (9.98)
    3.6
    (8.12)
    2.8
    (8.99)
    week 8
    2.7
    (10.67)
    2.3
    (9.02)
    2.2
    (8.79)
    week 12
    3.6
    (9.77)
    3.4
    (5.00)
    3.0
    (8.71)
    week 16
    3.3
    (13.24)
    4.7
    (8.84)
    1.9
    (11.90)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments statistical analysis at week 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.296
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 1.2
    Confidence Interval (2-Sided) 95%
    -0.9 to 3.3
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments statistical analysis at week 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.570
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 3.6
    Confidence Interval (2-Sided) 95%
    1.5 to 5.7
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, rhNGF 20 μg/ml BID + Vehicle OD
    Comments statistical analysis at week 8
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.754
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 2.7
    Confidence Interval (2-Sided) 95%
    0.5 to 4.9
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments statistical analysis at week 8
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.972
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 2.3
    Confidence Interval (2-Sided) 95%
    0.0 to 4.5
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, rhNGF 20 μg/ml BID + Vehicle OD
    Comments statistical analysis at week 12
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.793
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 3.4
    Confidence Interval (2-Sided) 95%
    1.4 to 5.3
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments statistical analysis at week 12
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.766
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 3.4
    Confidence Interval (2-Sided) 95%
    1.5 to 5.3
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml TID, Vehicle TID
    Comments statistical analysis at week 16
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.458
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 3.3
    Confidence Interval (2-Sided) 95%
    0.6 to 6.0
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 8
    Statistical Analysis Overview Comparison Group Selection rhNGF 20 μg/ml BID + Vehicle OD, Vehicle TID
    Comments statistical analysis at week 16
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.147
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Least square mean difference
    Estimated Value 4.6
    Confidence Interval (2-Sided) 95%
    2.0 to 7.3
    Parameter Dispersion Type:
    Value:
    Estimation Comments

    Adverse Events

    Time Frame From Screening day to week 16
    Adverse Event Reporting Description More specifically, adverse events are assessed at Screening day, Visit 1 Day 1), Visit 2 (Day 14), Visit 3 (Day 28), Visit 4 (Day 56), Visit 5 (Day 84), Visit 6 (Day 112).
    Arm/Group Title rhNGF 20 μg/ml TID - Treatment Period rhNGF 20 μg/ml BID + Vehicle OD - Treatment Period Vehicle TID - Treatment Period rhNGF 20 μg/ml TID - Follow-up Period rhNGF 20 μg/ml BID + Vehicle OD - Follow-up Period Vehicle TID - Follow up Period
    Arm/Group Description One drop of rhNGF 20 μg/ml will be instilled in both eyes three times daily (every 6-8 hours) rhNGF 20 μg/ml: one drop of rhNGF 20 μg/ml will be instilled in both eyes three times daily (every 6-8 hours) One drop of rhNGF 20 μg/ml will be instilled in both eyes two times daily (BID) plus one drop (40 μL) of vehicle will be instilled in both eyes once daily (OD) (every 6-8 hours) rhNGF 20 μg/ml + vehicle: one drop of rhNGF 20 μg/ml will be instilled in both eyes two times daily plus one drop (40 μL) of vehicle will be instilled in both eyes once daily (every 6-8 hours). rhNGF will be instilled in the morning and in the evening while the vehicle will be instilled in the afternoon. Vehicle eye one drop will be instilled in both eyes three times daily (every 6-8 hours) Vehicle: one drop of vehicle will be instilled in both eyes three times daily (every 6-8 hours) One drop of rhNGF 20 μg/ml will be instilled in both eyes three times daily (every 6-8 hours) rhNGF 20 μg/ml: one drop of rhNGF 20 μg/ml will be instilled in both eyes three times daily (every 6-8 hours) One drop of rhNGF 20 μg/ml will be instilled in both eyes two times daily (BID) plus one drop (40 μL) of vehicle will be instilled in both eyes once daily (OD) (every 6-8 hours) rhNGF 20 μg/ml + vehicle: one drop of rhNGF 20 μg/ml will be instilled in both eyes two times daily plus one drop (40 μL) of vehicle will be instilled in both eyes once daily (every 6-8 hours). rhNGF will be instilled in the morning and in the evening while the vehicle will be instilled in the afternoon. Vehicle eye one drop will be instilled in both eyes three times daily (every 6-8 hours) Vehicle: one drop of vehicle will be instilled in both eyes three times daily (every 6-8 hours)
    All Cause Mortality
    rhNGF 20 μg/ml TID - Treatment Period rhNGF 20 μg/ml BID + Vehicle OD - Treatment Period Vehicle TID - Treatment Period rhNGF 20 μg/ml TID - Follow-up Period rhNGF 20 μg/ml BID + Vehicle OD - Follow-up Period Vehicle TID - Follow up Period
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/85 (0%) 0/84 (0%) 0/88 (0%) 0/85 (0%) 0/84 (0%) 0/88 (0%)
    Serious Adverse Events
    rhNGF 20 μg/ml TID - Treatment Period rhNGF 20 μg/ml BID + Vehicle OD - Treatment Period Vehicle TID - Treatment Period rhNGF 20 μg/ml TID - Follow-up Period rhNGF 20 μg/ml BID + Vehicle OD - Follow-up Period Vehicle TID - Follow up Period
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/85 (0%) 0/84 (0%) 0/88 (0%) 1/85 (1.2%) 0/84 (0%) 1/88 (1.1%)
    Cardiac disorders
    Atrial fibrillation 0/85 (0%) 0 0/84 (0%) 0 0/88 (0%) 0 0/85 (0%) 0 0/84 (0%) 0 1/88 (1.1%) 1
    Injury, poisoning and procedural complications
    Humerus fracture 0/85 (0%) 0 0/84 (0%) 0 0/88 (0%) 0 1/85 (1.2%) 1 0/84 (0%) 0 0/88 (0%) 0
    Other (Not Including Serious) Adverse Events
    rhNGF 20 μg/ml TID - Treatment Period rhNGF 20 μg/ml BID + Vehicle OD - Treatment Period Vehicle TID - Treatment Period rhNGF 20 μg/ml TID - Follow-up Period rhNGF 20 μg/ml BID + Vehicle OD - Follow-up Period Vehicle TID - Follow up Period
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 65/85 (76.5%) 60/84 (71.4%) 26/88 (29.5%) 19/85 (22.4%) 19/84 (22.6%) 18/88 (20.5%)
    Ear and labyrinth disorders
    Ear pain 1/85 (1.2%) 1 0/84 (0%) 0 0/88 (0%) 0 0/85 (0%) 0 0/84 (0%) 0 0/88 (0%) 0
    Eye disorders
    Asthenopia 0/85 (0%) 0 1/84 (1.2%) 1 0/88 (0%) 0 0/85 (0%) 0 0/84 (0%) 0 0/88 (0%) 0
    Blepharitis 0/85 (0%) 0 0/84 (0%) 0 0/88 (0%) 0 1/85 (1.2%) 1 1/84 (1.2%) 1 0/88 (0%) 0
    Blepharospasm 1/85 (1.2%) 1 0/84 (0%) 0 0/88 (0%) 0 0/85 (0%) 0 0/84 (0%) 0 0/88 (0%) 0
    Chalazion 0/85 (0%) 0 0/84 (0%) 0 0/88 (0%) 0 0/85 (0%) 0 2/84 (2.4%) 3 1/88 (1.1%) 1
    Conjunctival Disorder 0/85 (0%) 0 1/84 (1.2%) 1 0/88 (0%) 0 0/85 (0%) 0 0/84 (0%) 0 0/88 (0%) 0
    Conjunctival Haemorrhage 0/85 (0%) 0 0/84 (0%) 0 0/88 (0%) 0 1/85 (1.2%) 1 0/84 (0%) 0 0/88 (0%) 0
    Conjunctival Hyperaemia 1/85 (1.2%) 1 2/84 (2.4%) 2 1/88 (1.1%) 1 0/85 (0%) 0 0/84 (0%) 0 0/88 (0%) 0
    Diplopia 0/85 (0%) 0 1/84 (1.2%) 1 0/88 (0%) 0 0/85 (0%) 0 1/84 (1.2%) 1 0/88 (0%) 0
    Dry Eye 1/85 (1.2%) 2 3/84 (3.6%) 3 5/88 (5.7%) 6 2/85 (2.4%) 2 0/84 (0%) 0 1/88 (1.1%) 1
    Erythema Of Eyelid 0/85 (0%) 0 1/84 (1.2%) 2 1/88 (1.1%) 1 0/85 (0%) 0 1/84 (1.2%) 3 0/88 (0%) 0
    Eye Allergy 0/85 (0%) 0 0/84 (0%) 0 0/88 (0%) 0 0/85 (0%) 0 1/84 (1.2%) 1 0/88 (0%) 0
    Eye Discharge 1/85 (1.2%) 1 0/84 (0%) 0 0/88 (0%) 0 1/85 (1.2%) 1 0/84 (0%) 0 0/88 (0%) 0
    Eye Disorder 0/85 (0%) 0 1/84 (1.2%) 1 0/88 (0%) 0 0/85 (0%) 0 0/84 (0%) 0 0/88 (0%) 0
    Eye Irritation 2/85 (2.4%) 2 5/84 (6%) 14 5/88 (5.7%) 6 1/85 (1.2%) 1 2/84 (2.4%) 5 4/88 (4.5%) 4
    Eye Pain 54/85 (63.5%) 68 42/84 (50%) 73 4/88 (4.5%) 5 1/85 (1.2%) 1 1/84 (1.2%) 1 1/88 (1.1%) 1
    Eye Pruritus 2/85 (2.4%) 4 2/84 (2.4%) 2 1/88 (1.1%) 2 2/85 (2.4%) 2 1/84 (1.2%) 1 1/88 (1.1%) 1
    Eye Swelling 1/85 (1.2%) 1 2/84 (2.4%) 2 0/88 (0%) 0 0/85 (0%) 0 0/84 (0%) 0 0/88 (0%) 0
    Eyelid Disorder 1/85 (1.2%) 4 3/84 (3.6%) 3 0/88 (0%) 0 0/85 (0%) 0 0/84 (0%) 0 0/88 (0%) 0
    Eyelid Irritation 0/85 (0%) 0 0/84 (0%) 0 1/88 (1.1%) 1 0/85 (0%) 0 0/84 (0%) 0 1/88 (1.1%) 1
    Eyelid Oedema 1/85 (1.2%) 1 2/84 (2.4%) 2 0/88 (0%) 0 0/85 (0%) 0 0/84 (0%) 0 0/88 (0%) 0
    Eyelid Pain 3/85 (3.5%) 6 9/84 (10.7%) 15 0/88 (0%) 0 0/85 (0%) 0 0/84 (0%) 0 0/88 (0%) 0
    Foreign Body Sensation In Eyes 1/85 (1.2%) 1 3/84 (3.6%) 3 0/88 (0%) 0 0/85 (0%) 0 0/84 (0%) 0 0/88 (0%) 0
    Lacrimation Increased 0/85 (0%) 0 0/84 (0%) 0 0/88 (0%) 0 0/85 (0%) 0 0/84 (0%) 0 1/88 (1.1%) 1
    Meibomian Gland Dysfunction 0/85 (0%) 0 0/84 (0%) 0 0/88 (0%) 0 0/85 (0%) 0 1/84 (1.2%) 2 0/88 (0%) 0
    Ocular Discomfort 6/85 (7.1%) 9 4/84 (4.8%) 4 0/88 (0%) 0 1/85 (1.2%) 1 0/84 (0%) 0 0/88 (0%) 0
    Ocular Hyperaemia 2/85 (2.4%) 2 3/84 (3.6%) 4 3/88 (3.4%) 4 2/85 (2.4%) 2 1/84 (1.2%) 1 1/88 (1.1%) 1
    Photophobia 6/85 (7.1%) 6 4/84 (4.8%) 4 0/88 (0%) 0 0/85 (0%) 0 2/84 (2.4%) 2 0/88 (0%) 0
    Posterior Capsule Opacification 0/85 (0%) 0 0/84 (0%) 0 0/88 (0%) 0 0/85 (0%) 0 1/84 (1.2%) 1 0/88 (0%) 0
    Refraction Disorder 1/85 (1.2%) 1 0/84 (0%) 0 0/88 (0%) 0 0/85 (0%) 0 0/84 (0%) 0 0/88 (0%) 0
    Swelling Of Eyelid 1/85 (1.2%) 1 6/84 (7.1%) 6 1/88 (1.1%) 1 1/85 (1.2%) 1 0/84 (0%) 0 0/88 (0%) 0
    Vision Blurred 3/85 (3.5%) 3 2/84 (2.4%) 2 1/88 (1.1%) 2 1/85 (1.2%) 1 2/84 (2.4%) 2 2/88 (2.3%) 2
    Visual Acuity Reduced 1/85 (1.2%) 1 1/84 (1.2%) 1 0/88 (0%) 0 0/85 (0%) 0 0/84 (0%) 0 0/88 (0%) 0
    Visual Impairment 1/85 (1.2%) 1 0/84 (0%) 0 0/88 (0%) 0 0/85 (0%) 0 1/84 (1.2%) 1 0/88 (0%) 0
    Vitreous Floaters 0/85 (0%) 0 0/84 (0%) 0 1/88 (1.1%) 1 0/85 (0%) 0 0/84 (0%) 0 0/88 (0%) 0
    Gastrointestinal disorders
    Constipation 1/85 (1.2%) 1 0/84 (0%) 0 0/88 (0%) 0 1/85 (1.2%) 1 0/84 (0%) 0 0/88 (0%) 0
    Inguinal Hernia 0/85 (0%) 0 0/84 (0%) 0 0/88 (0%) 0 0/85 (0%) 0 1/84 (1.2%) 1 0/88 (0%) 0
    Nausea 3/85 (3.5%) 4 0/84 (0%) 0 0/88 (0%) 0 0/85 (0%) 0 0/84 (0%) 0 0/88 (0%) 0
    General disorders
    Instillation Site Irritation 0/85 (0%) 0 1/84 (1.2%) 1 0/88 (0%) 0 0/85 (0%) 0 0/84 (0%) 0 0/88 (0%) 0
    Instillation Site Pain 2/85 (2.4%) 2 1/84 (1.2%) 1 0/88 (0%) 0 1/85 (1.2%) 1 0/84 (0%) 0 0/88 (0%) 0
    Infections and infestations
    Bronchitis 0/85 (0%) 0 0/84 (0%) 0 0/88 (0%) 0 0/85 (0%) 0 2/84 (2.4%) 2 0/88 (0%) 0
    Hordeolum 1/85 (1.2%) 1 0/84 (0%) 0 0/88 (0%) 0 0/85 (0%) 0 2/84 (2.4%) 3 0/88 (0%) 0
    Influenza 0/85 (0%) 0 1/84 (1.2%) 1 0/88 (0%) 0 0/85 (0%) 0 0/84 (0%) 0 1/88 (1.1%) 1
    Kidney Infection 0/85 (0%) 0 0/84 (0%) 0 0/88 (0%) 0 0/85 (0%) 0 1/84 (1.2%) 1 0/88 (0%) 0
    Nasopharyngitis 0/85 (0%) 0 1/84 (1.2%) 1 2/88 (2.3%) 2 1/85 (1.2%) 1 0/84 (0%) 0 1/88 (1.1%) 1
    Sinusitis 1/85 (1.2%) 1 1/84 (1.2%) 1 3/88 (3.4%) 3 1/85 (1.2%) 1 0/84 (0%) 0 1/88 (1.1%) 1
    Upper Respiratory Tract 1/85 (1.2%) 1 0/84 (0%) 0 0/88 (0%) 0 3/85 (3.5%) 3 0/84 (0%) 0 1/88 (1.1%) 1
    Urinary Tract Infection 0/85 (0%) 0 0/84 (0%) 0 0/88 (0%) 0 1/85 (1.2%) 1 0/84 (0%) 0 1/88 (1.1%) 1
    Viral Infection 0/85 (0%) 0 0/84 (0%) 0 0/88 (0%) 0 1/85 (1.2%) 1 0/84 (0%) 0 0/88 (0%) 0
    Injury, poisoning and procedural complications
    Back Injury 0/85 (0%) 0 0/84 (0%) 0 0/88 (0%) 0 1/85 (1.2%) 1 0/84 (0%) 0 0/88 (0%) 0
    Humerus Fracture 0/85 (0%) 0 0/84 (0%) 0 0/88 (0%) 0 1/85 (1.2%) 1 0/84 (0%) 0 0/88 (0%) 0
    Ligament Sprain 0/85 (0%) 0 0/84 (0%) 0 0/88 (0%) 0 0/85 (0%) 0 0/84 (0%) 0 1/88 (1.1%) 1
    Superficial Injury Of Eye 0/85 (0%) 0 0/84 (0%) 0 1/88 (1.1%) 1 0/85 (0%) 0 0/84 (0%) 0 0/88 (0%) 0
    Musculoskeletal and connective tissue disorders
    Arthritis 1/85 (1.2%) 1 0/84 (0%) 0 0/88 (0%) 0 0/85 (0%) 0 0/84 (0%) 0 0/88 (0%) 0
    Bursitis 0/85 (0%) 0 0/84 (0%) 0 0/88 (0%) 0 1/85 (1.2%) 1 0/84 (0%) 0 0/88 (0%) 0
    Tendonitis 0/85 (0%) 0 2/84 (2.4%) 2 0/88 (0%) 0 0/85 (0%) 0 0/84 (0%) 0 0/88 (0%) 0
    Nervous system disorders
    Dizziness 0/85 (0%) 0 0/84 (0%) 0 1/88 (1.1%) 1 0/85 (0%) 0 0/84 (0%) 0 0/88 (0%) 0
    Headache 8/85 (9.4%) 9 5/84 (6%) 5 4/88 (4.5%) 4 0/85 (0%) 0 1/84 (1.2%) 1 0/88 (0%) 0
    Hypoaesthesia 0/85 (0%) 0 1/84 (1.2%) 1 0/88 (0%) 0 0/85 (0%) 0 0/84 (0%) 0 0/88 (0%) 0
    Migraine 0/85 (0%) 0 0/84 (0%) 0 0/88 (0%) 0 0/85 (0%) 0 1/84 (1.2%) 1 0/88 (0%) 0
    Migraine With Aura 1/85 (1.2%) 1 1/84 (1.2%) 2 1/88 (1.1%) 1 0/85 (0%) 0 0/84 (0%) 0 0/88 (0%) 0
    Renal and urinary disorders
    Bladder Prolapse 0/85 (0%) 0 0/84 (0%) 0 0/88 (0%) 0 0/85 (0%) 0 0/84 (0%) 0 1/88 (1.1%) 1
    Respiratory, thoracic and mediastinal disorders
    Asthma 0/85 (0%) 0 0/84 (0%) 0 0/88 (0%) 0 0/85 (0%) 0 1/84 (1.2%) 1 0/88 (0%) 0
    Cough 0/85 (0%) 0 0/84 (0%) 0 1/88 (1.1%) 1 0/85 (0%) 0 0/84 (0%) 0 0/88 (0%) 0
    Dysphonia 1/85 (1.2%) 1 0/84 (0%) 0 0/88 (0%) 0 0/85 (0%) 0 0/84 (0%) 0 0/88 (0%) 0
    Oropharyngeal Pain 1/85 (1.2%) 1 0/84 (0%) 0 0/88 (0%) 0 0/85 (0%) 0 0/84 (0%) 0 0/88 (0%) 0
    Sinus Congestion 0/85 (0%) 0 0/84 (0%) 0 1/88 (1.1%) 1 0/85 (0%) 0 0/84 (0%) 0 1/88 (1.1%) 1
    Throat Irritation 0/85 (0%) 0 0/84 (0%) 0 1/88 (1.1%) 1 0/85 (0%) 0 0/84 (0%) 0 0/88 (0%) 0
    Skin and subcutaneous tissue disorders
    Dermatitis 0/85 (0%) 0 0/84 (0%) 0 0/88 (0%) 0 0/85 (0%) 0 0/84 (0%) 0 1/88 (1.1%) 1
    Rash 0/85 (0%) 0 1/84 (1.2%) 1 0/88 (0%) 0 0/85 (0%) 0 0/84 (0%) 0 0/88 (0%) 0
    Vascular disorders
    Hot Flush 1/85 (1.2%) 1 0/84 (0%) 0 0/88 (0%) 0 0/85 (0%) 0 0/84 (0%) 0 0/88 (0%) 0
    Lymphoedema 0/85 (0%) 0 0/84 (0%) 0 0/88 (0%) 0 1/85 (1.2%) 1 0/84 (0%) 0 0/88 (0%) 0

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Maria De Pizzol, BSc
    Organization Dompé farmaceutici SpA
    Phone +39 02 583831
    Email info@pec.dompe.it
    Responsible Party:
    Dompé Farmaceutici S.p.A
    ClinicalTrials.gov Identifier:
    NCT03982368
    Other Study ID Numbers:
    • NGF0118
    First Posted:
    Jun 11, 2019
    Last Update Posted:
    Feb 8, 2022
    Last Verified:
    Jan 1, 2022