Clinical trial NCT03500549: Study to Evaluate the Efficacy and Safety of APL-2 in Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH)
Official title: A Phase III, Randomized, Multi-Center, Open-Label, Active-Comparator Controlled Study to Evaluate the Efficacy and Safety of APL-2 in Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Paroxysmal Nocturnal Hemoglobinuria
Lead sponsor: Apellis Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2018-04-18
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: Evaluation of the Efficacy and Safety of APL-2 in Patients with Paroxysmal Nocturnal Hemoglobinuria


Eligibility criteria: Inclusion Criteria:

* At least 18 years of age
* Primary diagnosis of PNH confirmed by high-sensitivity flow cytometry
* On treatment with eculizumab. Dose of eculizumab must have been stable for at least 3 months prior to the Screening Visit
* Hb \<10.5 g/dL at the Screening Visit
* Absolute reticulocyte count \> 1.0x ULN at the Screening Visit
* Platelet count of \>50,000/mm3 at the Screening Visit
* Absolute neutrophil count \>500/mm3 at the Screening Visit
* Vaccination against Neisseria meningitides types A, C, W, Y and B, Streptococcus pneumoniae and Haemophilus influenzae Type B (Hib) either within 2 years prior to Day 1 dosing, or within 14 days after starting treatment with APL-2. Unless documented evidence exists that subjects are non-responders to vaccination as evidenced by titers or display titer levels within acceptable local limits
* Women of child-bearing potential (WOCBP) must have a negative pregnancy test at the Screening and Day -28 Visit (Run-in Period) and must agree to use protocol defined methods of contraception for the duration of the study and 90 days after their last dose of study drug
* Males must agree to use protocol defined methods of contraception and agree to refrain from donating sperm for the duration of the study and 90 days after their last dose of study drug
* Willing and able to give informed consent
* Willing and able to self-administer APL-2 (administration by caregiver will be allowed)
* Have a body mass index (BMI) ≤35.0 kg/m2

Exclusion Criteria:

* Active bacterial infection that has not resolved within 14 week of Day -28 (first dose of APL-2)
* Receiving iron, folic acid, vitamin B12 and EPO, unless the dose is stable, in the 4 weeks prior to Screening
* Hereditary complement deficiency
* History of bone marrow transplantation
* History or presence of hypersensitivity or idiosyncratic reaction to compounds related to the investigational product or SC administration
* Participation in any other investigational drug trial or exposure to other investigational agent within 30 days or 5 half-lives (whichever is longer)
* Currently breast-feeding women
* Inability to cooperate or any condition that, in the opinion of the investigator, could increase the subject's risk of participating in the study or confound the outcome of the study

This study includes cardiac safety evaluations. The following cardiac eligibility criteria are necessary to avoid confounding the cardiac safety outcomes:

* History or family history of Long QT Syndrome or torsade de pointes, unexplained syncope, syncope from an uncorrected cardiac etiology, or family history of sudden death
* Myocardial infarction, CABG, coronary or cerebral artery stenting and /or angioplasty, stroke, cardiac surgery, or hospitalization for congestive heart failure within 3 months or greater than Class 2 Angina Pectoris or NYHA Heart Failure Class \>2
* QTcF \> 470 ms, PR \> 280 ms
* Mobitz II 2nd degree AV Block, 2:1 AV Block, High Grade AV Block, or Complete Heart Block unless the patient has an implanted pacemaker or implantable cardiac defibrillator (ICD) with backup pacing capabilities
* Receiving Class 1 or Class 3 antiarrhythmic agents, or arsenic, methadone, ondansetron or pentamidine at screening
* Receiving any other QTc-prolonging drugs (see Appendix 4 in Section 19.4), at a stable dose for less than 3 weeks prior to dosing
* Receiving prophylactic ciprofloxacin, erythromycin or azithromycin for less than one week prior to the first dose of study medication (must have a repeat screening ECG after one week of prophylactic antibiotics with QTcF \< 470 ms)

Primary outcomes:
measure: Least Squares (LS) Mean Change From Baseline to Week 16 in Hemoglobin (Hb) Level During the RCP
timeFrame: Baseline and Week 16
Secondary outcomes:
measure: Percentage of Subjects Who Did Not Require a Transfusion (Transfusion Avoidance) During the RCP
timeFrame: Day 1 to Week 16
measure: LS Mean Change From Baseline to Week 16 in Absolute Reticulocyte Count (ARC) During the RCP
timeFrame: Baseline and Week 16
measure: LS Mean Change From Baseline to Week 16 in Lactate Dehydrogenase (LDH) Level During the RCP
timeFrame: Baseline and Week 16
measure: LS Mean Change From Baseline to Week 16 in Functional Assessment of Chronic Illness Therapy (FACIT) - Fatigue Scale Score During the RCP
timeFrame: Baseline and Week 16
measure: Percentage of Subjects Who Achieved a Hb Response in the Absence of Transfusions at Week 16
timeFrame: Baseline and Week 16
measure: Percentage of Subjects Who Achieved Reticulocyte Normalization in the Absence of Transfusions at Week 16
timeFrame: Week 16
measure: Percentage of Subjects Who Achieved Hb Normalization in the Absence of Transfusions at Week 16
timeFrame: Week 16
measure: LS Mean Change From Baseline to Week 16 in Indirect Bilirubin Level During the RCP
timeFrame: Baseline and Week 16
measure: LS Mean Change From Baseline to Week 16 in Haptoglobin Level During the RCP
timeFrame: Baseline and Week 16
measure: LS Mean Change From Baseline to Week 16 in Linear Analog Scale Assessment (LASA) Scores During the RCP
timeFrame: Baseline and Week 16
measure: LS Mean Change From Baseline to Week 16 in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Core 30 Scale (QLQ-C30) Scores During the RCP
timeFrame: Baseline and Week 16
measure: Total Number of PRBC Units Transfused During the RCP
timeFrame: Day 1 to Week 16
measure: Mean Change From Baseline to Week 48 in Hb Level During the Treatment Period
timeFrame: Baseline and Week 48
measure: Mean Change From Week 17 to Week 48 in Hb Level During the Open-label Period
timeFrame: Week 17 and Week 48
measure: Mean Change From Baseline to Week 48 in ARC During the Treatment Period
timeFrame: Baseline and Week 48
measure: Mean Change From Week 17 to Week 48 in ARC During the Open-label Period
timeFrame: Week 17 and Week 48
measure: Mean Change From Baseline to Week 48 in LDH Level During the Treatment Period
timeFrame: Baseline and Week 48
measure: Mean Change From Week 17 to Week 48 in LDH Level During the Open-label Period
timeFrame: Week 17 and Week 48
measure: Mean Change From Baseline to Week 48 in FACIT-Fatigue Scale Score During the Treatment Period
timeFrame: Baseline and Week 48
measure: Mean Change From Week 17 to Week 48 in FACIT-Fatigue Scale Score During the Open-label Period
timeFrame: Week 17 and Week 48
measure: Mean Change From Baseline to Week 48 in LASA Scores During the Treatment Period
timeFrame: Baseline and Week 48
measure: Mean Change From Week 17 to Week 48 in LASA Scores During the Open-label Period
timeFrame: Week 17 and Week 48
measure: Mean Change From Baseline to Week 48 in QLQ-C30 Scores During the Treatment Period
timeFrame: Baseline and Week 48
measure: Mean Change From Week 17 to Week 48 in QLQ-C30 Scores During the Open-label Period
timeFrame: Week 17 and Week 48
measure: Total Number of PRBC Units Transfused During the Open-Label Period
timeFrame: Week 17 to Week 48
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of Southern California
state: California
city: Santa Monica
country: United States
facility: Sarcoma Oncology Research Center
state: California
city: Denver
country: United States
facility: Denver Health
state: Colorado
city: Washington
country: United States
facility: Georgetown University Hospital
state: District of Columbia
city: Jacksonville
country: United States
facility: Cancer Specialists of North Florida
state: Florida
city: Miami Lakes
country: United States
facility: Lakes Research
state: Florida
city: Orange City
country: United States
facility: Mid Florida Hematology and Oncology
state: Florida
city: Atlanta
country: United States
facility: Winship Cancer Institute of Emory University
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Indianapolis
country: United States
facility: Investigative Clinical Research of Indiana
state: Indiana
city: Grand Rapids
country: United States
facility: Cancer & Hematology Centers of Western Michigan
state: Michigan
city: Bronx
country: United States
facility: New York Cancer & Blood Specialists
state: New York
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: East Setauket
country: United States
facility: New York Cancer & Blood Specialists
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Corvallis
country: United States
facility: Good Samaritan Hospital
state: Oregon
city: Knoxville
country: United States
facility: University of Tennessee Medical Center
state: Tennessee
city: Memphis
country: United States
facility: Baptist Cancer Center
state: Tennessee
city: Tyler
country: United States
facility: HOPE Cancer Center of East Texas
state: Texas
city: Melbourne
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Woluwe-Saint-Lambert
country: Belgium
facility: Cliniques Universitaires Saint-Luc
state: Vlaams-Brabant
city: Roeselare
country: Belgium
facility: AZ Delta Campus Wilgenstraat
state: West-Vlaanderen
city: Edmonton
country: Canada
facility: University of Alberta
state: Alberta
city: Toronto
country: Canada
facility: Toronto General Hospital
state: Ontario
city: Annecy
country: France
facility: Centre Hospitalier Annecy Genevois
city: Chalon-sur-Saône
country: France
facility: Centre Hospitalier William Morey
city: Lille
country: France
facility: Centre Hospitalier Universitaire de Lille
city: Marseille
country: France
facility: Institut Paoli-Calmettes Marseille
city: Paris
country: France
facility: Hôpital Saint-Louis
city: Pierre-Bénite
country: France
facility: Centre Hospitalier Lyon Sud
city: Saint-Quentin
country: France
facility: Centre Hospitalier de Saint-Quentin
city: Toulouse
country: France
facility: Institut Universitaire du Cancer Toulouse - Oncopole
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm
state: Baden-Württemberg
city: Aachen
country: Germany
facility: Uniklinik RWTH Aachen
state: North Rhine-Westphalia
city: Essen
country: Germany
facility: Universitätsklinikum Essen
state: North Rhine-Westphalia
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg Eppendorf
city: Nagoya
country: Japan
facility: Japanese Red Cross Nagoya Daiichi Hospital
state: Aichi
city: Showa-ku
country: Japan
facility: Japanese Red Cross Nagoya Daini Hospital
state: Aichi
city: Tsukuba
country: Japan
facility: University of Tsukuba Hospital
state: Ibaraki
city: Matsumoto
country: Japan
facility: Shinshu University Hospital
state: Nagano
city: Okayama-shi
country: Japan
facility: Okayama University Hospital
state: Okayama
city: Bunkyo-ku
country: Japan
facility: Juntendo University Hospital
state: Tokyo
city: Shinagawa-ku
country: Japan
facility: NTT Medical Center Tokyo
state: Tokyo
city: Tanabe
country: Japan
facility: Kinan Hospital
state: Wakayama
city: Bucheon
country: Korea, Republic of
facility: Soonchunhyang University Bucheon Hospital
city: Daejeon
country: Korea, Republic of
facility: Chungnam National University Hospital
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Saint Petersburg
country: Russian Federation
facility: Pavlov First Saint Petersburg State Medical University of Russian Ministry of Health
city: Saint Petersburg
country: Russian Federation
facility: Pavlov First Saint Petersburg State Medical University
city: Tyumen
country: Russian Federation
facility: Institution of Health Care of Tyumen Region
city: Las Palmas De Gran Canaria
country: Spain
facility: Hospital Universitario de Gran Canaria Dr. Negrín
city: Valencia
country: Spain
facility: Hospital Universitario Politécnico La Fe
city: Leeds
country: United Kingdom
facility: St. James' Institute of Oncology, Leeds Teaching Hospitals
Study officials:
References:
citation: de Latour RP, Szer J, Weitz IC, Roth A, Hochsmann B, Panse J, Usuki K, Griffin M, Kiladjian JJ, de Castro CM, Nishimori H, Ajayi T, Al-Adhami M, Deschatelets P, Francois C, Grossi F, Risitano AM, Hillmen P. Pegcetacoplan versus eculizumab in patients with paroxysmal nocturnal haemoglobinuria (PEGASUS): 48-week follow-up of a randomised, open-label, phase 3, active-comparator, controlled trial. Lancet Haematol. 2022 Sep;9(9):e648-e659. doi: 10.1016/S2352-3026(22)00210-1.
citation: Cella D, Sarda SP, Hsieh R, Fishman J, Hakimi Z, Hoffman K, Al-Adhami M, Nazir J, Cutts K, Lenderking WR. Changes in hemoglobin and clinical outcomes drive improvements in fatigue, quality of life, and physical function in patients with paroxysmal nocturnal hemoglobinuria: post hoc analyses from the phase III PEGASUS study. Ann Hematol. 2022 Sep;101(9):1905-1914. doi: 10.1007/s00277-022-04887-8. Epub 2022 Jul 23.
citation: Hakimi Z, Wilson K, McAughey E, Pochopien M, Wojciechowski P, Toumi M, Knight C, Sarda SP, Patel N, Wiseman C, de Castro NP, Nazir J, Kelly RJ. The cost-effectiveness, of pegcetacoplan compared with ravulizumab for the treatment of paroxysmal nocturnal hemoglobinuria, in a UK setting. J Comp Eff Res. 2022 Sep;11(13):969-985. doi: 10.2217/cer-2022-0076. Epub 2022 Jul 7.
citation: Bhak RH, Mody-Patel N, Baver SB, Kunzweiler C, Yee CW, Sundaresan S, Swartz N, Duh MS, Krishnan S, Sarda SP. Comparative effectiveness of pegcetacoplan versus ravulizumab in patients with paroxysmal nocturnal hemoglobinuria previously treated with eculizumab: a matching-adjusted indirect comparison. Curr Med Res Opin. 2021 Nov;37(11):1913-1923. doi: 10.1080/03007995.2021.1971182. Epub 2021 Sep 3.
citation: Hillmen P, Szer J, Weitz I, Roth A, Hochsmann B, Panse J, Usuki K, Griffin M, Kiladjian JJ, de Castro C, Nishimori H, Tan L, Hamdani M, Deschatelets P, Francois C, Grossi F, Ajayi T, Risitano A, Peffault de Latour R. Pegcetacoplan versus Eculizumab in Paroxysmal Nocturnal Hemoglobinuria. N Engl J Med. 2021 Mar 18;384(11):1028-1037. doi: 10.1056/NEJMoa2029073.