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NCT01527500

Intravitreal LFG316 in Patients With Age-related Macular Degeneration (AMD)

Completed Phase 2 Results posted Last updated 5 January 2021
What this trial tests

Phase 2 trial testing LFG316 in Geographic Atrophy in 158 participants. Completed in 24 June 2015.

Timeline
25 January 2012
Primary endpoint
24 June 2015
24 June 2015

Quick facts

Lead sponsorNovartis Pharmaceuticals
PhasePhase 2
StatusCompleted
Study typeINTERVENTIONAL
Allocationrandomized
Designparallel
Maskingsingle
Primary purposetreatment
Enrollment158
Start date25 January 2012
Primary completion24 June 2015
Estimated completion24 June 2015
Sites19 locations across United States

Drugs / interventions tested

Conditions studied

Sponsor

Novartis Pharmaceuticals — full company profile →

Who can join

55 and older, any sex, with Geographic Atrophy or Age-related Macular Degeneration. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Part A: Geographic Atrophy (GA) Lesion Growth Measured by Fundus Autofluorescence (FAF) From Baseline to Day 505 Primary · Day 1 to Day 505 (starting from the day of first intravitreal injection until Day 505)

Geographic atrophy (GA) lesion growth measured by fundus autofluorescence (FAF) from baseline to Day 505.

GroupValue95% CI
LFG3161.95± 1.01
Sham1.58± 1.12
Part A: Change From Baseline in GA Lesions Growth Measured by Fundus Autofluorescence Secondary · Day 1 to Day 169 and Day 505 (starting from the day of first intravitreal injection until Day 505)

Mean change in GA lesion growth from baseline to Day 169 and Day 505.

Day 169 (n=68, 37)
GroupValue95% CI
LFG3160.99± 0.60
Sham0.88± 0.77
Day 505 (n=38, 18)
GroupValue95% CI
LFG3162.78± 1.28
Sham2.03± 1.00
Part A: Change in Best Corrected Visual Acuity (BCVA) as Measured by the EDTRS (Early Treatment of Diabetic Retinopathy Study) Scale From Baseline to Days 169, 337 & 505 in Patients Receiving Every 28 Days, Successive IVT Doses of LFG316 Compared to Sham Secondary · Baseline Day 1, Day 169, Day 337 to Day 505

Part A: Summary of best corrected visual acuity over time, statistical analysis of change in best corrected visual acuity over time Parameter: Visual Acuity (EDTRS letter) BCVA scale is 0-100, worst is 0 and best 100 Eye: STUDY

Baseline Day 1 (n=74, 38)
GroupValue95% CI
LFG31643.91± 12.93
Sham40.26± 14.97
Day 169 (n=71, 36)
GroupValue95% CI
LFG31648.38± 11.05
Sham42.50± 15.14
Day 337 (n=53, 30)
GroupValue95% CI
LFG31647.49± 11.25
Sham42.97± 14.23
Day 505 (n=40, 23)
GroupValue95% CI
LFG31644.73± 11.29
Sham43.78± 14.11
Part A: Summary of Best Corrected Visual Acuity Over Time, Statistical Analysis of Change in Best Corrected Visual Acuity Over Time Parameter: Visual Acuity (EDTRS Letter) BCVA Scale is 0-100, Worst is 0 and Best 100 Eye: FELLOW Secondary · Baseline Day 1, Day 169, Day 337 to Day 505

Part A: Summary of best corrected visual acuity over time, statistical analysis of change in best corrected visual acuity over time Parameter: Visual Acuity (EDTRS letter) BCVA scale is 0-100, worst is 0 and best 100 Eye: FELLOW

Baseline Day 1 (n=74, 38)
GroupValue95% CI
LFG31654.66± 22.02
Sham55.13± 18.27
Day 169 (n=71, 36)
GroupValue95% CI
LFG31654.59± 21.92
Sham57.33± 17.89
Day 337 (n=53, 30)
GroupValue95% CI
LFG31652.75± 21.66
Sham53.87± 18.83
Day 505 (n=40, 23)
GroupValue95% CI
LFG31650.95± 20.67
Sham49.87± 19.35
Part A: Concentrations of Total LFG316 in Blood During the Course of the Study Secondary · Day 1 to Day 559 (starting from the day of first intravitreal injection to day 559)

Summary statistic of total LFG316 concentrations (pharmacokinetic analysis set) n=number of participants, h=hours after the last administered dose e.g.; 0.0 means just before dosing. If the mean concentration is 0.00, that means there is no drug in the bloodstream

Day 1 (n=99), h=0
GroupValue95% CI
LFG3160.00± 0.00
Day 1(n= 97), h= 24
GroupValue95% CI
LFG316293± 332
Day 1(n=91), h=336
GroupValue95% CI
LFG316560± 238
Day 29 (n=94), h=0
GroupValue95% CI
LFG316289± 214
Day 57 (n=96), h=0
GroupValue95% CI
LFG316382± 218
Day 85 (n=93), h=0
GroupValue95% CI
LFG316436± 210
Day 113 (n=83), h=0
GroupValue95% CI
LFG316433± 219
Day 141 (n=84), h=0
GroupValue95% CI
LFG316451± 218
Part A: Concentrations of Total C5 in Blood During the Course of the Study Secondary · Day 1 to Day 559 (starting from the day of first intravitreal injection to day 559)

Summary statistic of total C5 concentrations n=number of participants, h=scheduled sampling time

Day 1 (n=99, 51), h=0
GroupValue95% CI
LFG316147000± 28900
Sham142000± 25500
(n= 97, 51), h= 24
GroupValue95% CI
LFG316143000± 31200
Sham139000± 27600
(n=91, 49), h=336
GroupValue95% CI
LFG316149000± 41100
Sham136000± 25600
Day 29 (n=94, 47), h=0
GroupValue95% CI
LFG316145000± 31200
Sham142000± 33900
Day 57 (n=96, 49), h=0
GroupValue95% CI
LFG316147000± 29300
Sham148000± 40400
Day 85 (n=93, 46), h=0
GroupValue95% CI
LFG316154000± 42500
Sham144000± 39100
Day 113 (n=83, 49), h=0
GroupValue95% CI
LFG316153000± 46200
Sham146000± 42100
Day 141 (n=84, 45), h=0
GroupValue95% CI
LFG316144000± 32600
Sham141000± 25600
Part A: Sensitivity Analysis of the Primary End Point: Mixed Effects Model for Repeated Measurements on GA Lesion Growth Measured by Fundus Autoflourescence Primary · The primary objective was from Day 1 to Day 337, however data was captured to Day 505 as exploratory objective

Number is the Estimated Difference (95% CI) in lesion size.

Bilateral Day 169
GroupValue95% CI
LFG3160.975.828 – 1.122
Sham0.9130.712 – 1.114
LFG316 5 Mg-Sham0.062-0.184 – 0.308
Bilateral Day 337
GroupValue95% CI
LFG3161.8251.584 – 2.065
Sham1.7101.379 – 2.041
LFG316 5 Mg-Sham0.115-0.292 – 0.522
Bilateral Day 505
GroupValue95% CI
LFG3162.6742.314 – 3.034
Sham2.5062.012 – 3.001
LFG316 5 Mg-Sham0.168-0.433 – 0.778
Overall Day 169
GroupValue95% CI
LFG3161.0360.891 – 1.181
Sham0.9370.718 – 1.156
LFG316 5 Mg-Sham0.099-0.160 – 0.357
Overall Day 337
GroupValue95% CI
LFG3161.8851.646 – 2.124
Sham1.7341.397 – 2.070
LFG316 5 Mg-Sham0.152-0.259 – 0.562
Overall Day 505
GroupValue95% CI
LFG3162.7352.376 – 3.094
Sham2.5302.035 – 3.025
LFG316 5 Mg-Sham0.205-0.405 – 0.814
Part B: AUC (Area Under the Curve) - Summary Statistics for PK Parameters Secondary · Day 1 to Day 85 (starting from the day of first intravitreal injection to day 85)

Summary statistic of total LFG316 concentrations (pharmacokinetic analysis set) n=number of participants, h=scheduled sampling time

AUCall (hr*ng/mL)
GroupValue95% CI
LFG316743000± 241000
AUClast (hr*ng/mL)
GroupValue95% CI
LFG316600000± 212000
Part B: Safety and Tolerability of a Single Intravitreal (IVT) Dose of 10 mg/100 μL of LFG316 in Patients With Advanced AMD). Primary · Day 1 to Day 85

This primary outcome (for Part B) is reported under the Adverse Events section.

Total # Affected by any Serious Adverse Event
GroupValue95% CI
Part A - LFG316 5mg27
Sham - Part A11
Part B - LFG316 10mg1
Sham - Part B0
Total # at Risk by any Serious Adverse Event
GroupValue95% CI
Part A - LFG316 5mg99
Sham - Part A51
Part B - LFG316 10mg7
Sham - Part B1
Tmax (hr) Secondary · Day 1 to Day 85 (starting from the day of first intravitreal injection to day 85)

PART B: Tmax (Time of Maximum concentration observed) This is the highest concentration of drug in the blood that is measured after a dose. Cmax usually happens within a few hours after the dose is taken. The time that Cmax happens is referred to as Tmax. For some antiretroviral drugs, a high Cmax is thought to increase the risk of side effects from the drug.

GroupValue95% CI
LFG316213119 – 311
Part B: Cmax - Summary Statistic for PK Parameters Secondary · Day 1 to Day 85 (starting from the day of first intravitreal injection to day 85)

Summary statistic for Part B of total LFG316 concentrations (pharmacokinetic analysis set) Cmax is the maximum (or peak) serum concentration that a drug achieves in a specified compartment or test area of the body after the drug has been administrated and before the administration of a second dose

GroupValue95% CI
LFG3161010± 213
Part B: Cmax_D - Summary Statistic for PK Parameters Secondary · Day 1 to Day 85 (starting from the day of first intravitreal injection to day 85)

Cmax\_D=ng/mL/mg

GroupValue95% CI
LFG316101± 21.3

Adverse events — posted to ClinicalTrials.gov

Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Part A - LFG316 5mg
Serious: 27/99 (27%)
Deaths:
Part A - Sham
Serious: 11/51 (22%)
Deaths:
Part B - LFG316 10mg
Serious: 1/7 (14%)
Deaths:
Part B - Sham
Serious: 0/1 (0%)
Deaths:

Serious adverse events (58 terms)

ReactionSystemPart A - LFG316 5mgPart A - ShamPart B - LFG316 10mgPart B - Sham
Angina pectorisCardiac disorders
Coronary artery diseaseCardiac disorders
Abdominal pain upperGastrointestinal disorders
Endophthalmitis (Study Eye)Infections and infestations
Urinary tract infectionInfections and infestations
AnaemiaBlood and lymphatic system disorders
Immune thrombocytopenic purpuraBlood and lymphatic system disorders
Atrial fibrillationCardiac disorders
Atrioventricular block second degreeCardiac disorders
Cardiac failure congestiveCardiac disorders
CardiomyopathyCardiac disorders
VertigoEar and labyrinth disorders
Visual acuity reduced (Fellow Eye)Eye disorders
Visual acuity reduced (Study Eye)Eye disorders
ConstipationGastrointestinal disorders
Gastrointestinal haemorrhageGastrointestinal disorders
Gastrooesophageal reflux diseaseGastrointestinal disorders
Small intestinal obstructionGastrointestinal disorders
Umbilical herniaGastrointestinal disorders
Upper gastrointestinal haemorrhageGastrointestinal disorders
VomitingGastrointestinal disorders
Non-cardiac chest painGeneral disorders
CellulitisInfections and infestations
Clostridium difficile infectionInfections and infestations
CystitisInfections and infestations
Other adverse events (343 terms — click to expand)

ReactionSystemPart A - LFG316 5mgPart A - ShamPart B - LFG316 10mgPart B - Sham
Conjunctival haemorrhage (Study Eye)Eye disorders
Vitreous floaters (Study Eye)Eye disorders
Upper respiratory tract infectionInfections and infestations
Eye pain (Study Eye)Eye disorders
Eye irritation (Study Eye)Eye disorders
Foreign body sensation in eyes (Study Eye)Eye disorders
Vitreous detachment (Study Eye)Eye disorders
NauseaGastrointestinal disorders
NasopharyngitisInfections and infestations
HypertensionVascular disorders
BronchitisInfections and infestations
Visual acuity reduced (Study Eye)Eye disorders
AnaemiaBlood and lymphatic system disorders
Lacrimation increased (Study Eye)Eye disorders
ConstipationGastrointestinal disorders
Oedema peripheralGeneral disorders
FallInjury, poisoning and procedural complications
DizzinessNervous system disorders
Dry eye (Fellow Eye)Eye disorders
Dry eye (Study Eye)Eye disorders
VomitingGastrointestinal disorders
HeadacheNervous system disorders
HypothyroidismEndocrine disorders
Blepharitis (Study Eye)Eye disorders
Eye pruritus (Study Eye)Eye disorders
Ocular discomfort (Study Eye)Eye disorders
Posterior capsule opacification (Fellow Eye)Eye disorders
Punctate keratitis (Study Eye)Eye disorders
DiarrhoeaGastrointestinal disorders
HypersensitivityImmune system disorders
Intraocular pressure increased (Study Eye)Investigations
Pain in extremityMusculoskeletal and connective tissue disorders
Anterior chamber cell (Study Eye)Eye disorders
Conjunctival hyperaemia (Study Eye)Eye disorders
Posterior capsule opacification (Study Eye)Eye disorders
Vision blurred (Study Eye)Eye disorders
Visual acuity reduced (Fellow Eye)Eye disorders
Visual impairment (Study Eye)Eye disorders
Vitreous detachment (Fellow Eye)Eye disorders
Vitreous floaters (Fellow Eye)Eye disorders

Most-reported serious reactions: Angina pectoris, Coronary artery disease, Abdominal pain upper, Endophthalmitis (Study Eye), Urinary tract infection, Anaemia, Immune thrombocytopenic purpura, Atrial fibrillation.

Data from ClinicalTrials.gov NCT01527500 adverse events section.

Sponsor's own description

This study was conducted in two parts; Part A and Part B: Part B was initially planned to include two cohorts. Cohort 2 was cancelled following an interim analysis for efficacy in Part A of the study, and not due to any safety issues or concerns. Cohort 2 is not referred to again and part B cohort 1 is referred to as part B alone in the remainder of the document and is the subject of this report. Part B was conducted to assess the safety and tolerability of a single intravitreal (IVT) LFG316 10 mg/100 µL injection. There was no efficacy evaluation in Part B. The study employed a multicenter, randomized, sham - controlled, single masked design. Eight patients with advanced AMD were planned to be randomized in a 3:1 ratio to receive a single IVT dose of LFG316 (10 mg/100 µL) or sham injection. Patients assigned to a sham injection were treated the same as those assigned to LFG316, except that the hub of an empty syringe (without needle) was placed against the eye instead of the IVT injection.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. New insights into the immune functions of complement.
    Reis ES, Mastellos DC, Hajishengallis G, Lambris JD. · · 2019 · cited 357× · PMID 31048789 · DOI 10.1038/s41577-019-0168-x
  2. The renaissance of complement therapeutics.
    Ricklin D, Mastellos DC, Reis ES, Lambris JD. · · 2018 · cited 305× · PMID 29199277 · DOI 10.1038/nrneph.2017.156
  3. Clinical promise of next-generation complement therapeutics.
    Mastellos DC, Ricklin D, Lambris JD. · · 2019 · cited 255× · PMID 31324874 · DOI 10.1038/s41573-019-0031-6
  4. Complement in immune and inflammatory disorders: therapeutic interventions.
    Ricklin D, Lambris JD. · · 2013 · cited 180× · PMID 23564578 · DOI 10.4049/jimmunol.1203200
  5. Recent developments in the treatment of age-related macular degeneration.
    Holz FG, Schmitz-Valckenberg S, Fleckenstein M. · · 2014 · cited 149× · PMID 24691477 · DOI 10.1172/jci71029
  6. Treatments for dry age-related macular degeneration: therapeutic avenues, clinical trials and future directions.
    Cabral de Guimaraes TA, Daich Varela M, Georgiou M, Michaelides M. · · 2022 · cited 135× · PMID 33741584 · DOI 10.1136/bjophthalmol-2020-318452
  7. Targeting the complement system for the management of retinal inflammatory and degenerative diseases.
    Xu H, Chen M. · · 2016 · cited 129× · PMID 26948311 · DOI 10.1016/j.ejphar.2016.03.001
  8. The eye as a complement dysregulation hotspot.
    Clark SJ, Bishop PN. · · 2018 · cited 89× · PMID 28948331 · DOI 10.1007/s00281-017-0649-6

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