Clinical Trials Register

Summary
EudraCT Number:	2018-004220-11
Sponsor's Protocol Code Number:	APL2-308
National Competent Authority:	Poland - Office for Medicinal Products
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2019-05-13
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Poland - Office for Medicinal Products

A.2

EudraCT number

2018-004220-11

A.3

Full title of the trial

A Phase 3, Randomized, Multicenter, Open-Label, Controlled Study to Evaluate the Efficacy and Safety of APL-2 in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH)

Randomizowane, wieloośrodkowe, prowadzone metodą otwartej próby, kontrolowane badanie fazy 3 mające na celu ocenę skuteczności i bezpieczeństwa APL-2 u pacjentów z napadową hemoglobinurią nocną (PNH)

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A Research Study to Gather Scientific Information About the Efficacy and Safety of the Investigational Drug APL-2 In Treating Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH), a Disease Associated with Anemia, In a Randomly Assigned Comparison with the Current Standard of Care Treatment Approved for PNH

A.3.2

Name or abbreviated title of the trial where available

PRINCE

A.4.1

Sponsor's protocol code number

APL2-308

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Apellis Pharmaceuticals, Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Apellis Pharmaceuticals, Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Argint International Clinical Research & Development Services Kft.
B.5.2	Functional name of contact point	Clinical Trials Information
B.5.3	Address:
B.5.3.1	Street Address	Bölöni György u. 22.
B.5.3.2	Town/ city	Budapest
B.5.3.3	Post code	1021
B.5.3.4	Country	Hungary
B.5.6	E-mail	clinicaltrials@argintinternational.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/17/1873
D.3 Description of the IMP
D.3.1	Product name	APL-2
D.3.2	Product code	APL-2
D.3.4	Pharmaceutical form	Solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	pegcetacoplan
D.3.9.1	CAS number	2019171-69-6
D.3.9.2	Current sponsor code	APL-2
D.3.9.3	Other descriptive name	APL-2
D.3.9.4	EV Substance Code	SUB192794
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	54
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Paroxysmal Nocturnal Hemoglobinuria (PNH)

E.1.1.1

Medical condition in easily understood language

PNH is a rare disorder causing red blood cells to break down too early.

E.1.1.2

Therapeutic area

Diseases [C] - Blood and lymphatic diseases [C15]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	LLT
E.1.2	Classification code	10055629
E.1.2	Term	Paroxysmal nocturnal hemoglobinuria
E.1.2	System Organ Class	100000004857

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of this study is to evaluate the efficacy of APL-2, compared to SOC (excluding complement inhibitors), in patients with PNH, as assessed by:
• Hemoglobin stabilization defined as avoidance of a > 1 g/dl decrease in Hb levels from Baseline in the absence of transfusion through Week 26 (Yes/No)
AND
• Reduction in lactate dehydrogenase (LDH) level from Baseline to Week 26

E.2.2

Secondary objectives of the trial

• To evaluate the efficacy of APL-2, compared to SOC (excluding complement inhibitors), as assessed by:
o Hemoglobin response in the absence of transfusions (Hb response defined as a ≥1g/dL increase in Hb from Baseline at Week 26)
o Change from Baseline to Week 26 (W 26) in absolute reticulocyte count
o Change from Baseline to W 26 in Hb level
o Number of PRBC units transfused from Baseline to W 26
o Change from Baseline to W 26 in FACIT- Fatigue Scale score
o Normalization of Hb levels (≥1x ULN) from Baseline at W 26 in the absence of transfusions
o Normalization of LDH levels of ≤1 x the upper limit of normal from Week 4 to W 26 in the absence of transfusions
o Change from Baseline to W 26 in EORTC QLQ-C30 scores
o Change from Baseline to W 26 in LASA scale scores
o Change from Baseline to W 26 in LDH level
o Absolute reticulocyte count normalization (<1 x ULN) at W 26
o Time of failure of Hb stabilization
o Time to transfusion

• To evaluate the safety of APL-2

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

At Visit 1 screening, subjects must fulfill all of the following inclusion criteria to be eligible for participation in the study:
1. Be at least 18 years old (inclusive).
2. Have LDH ≥1.5 x ULN at the screening visit.
3. Have PNH diagnosis, confirmed by high sensitivity flow cytometry (granulocyte or monocyte clone >10%).
4. Have Hb less than the lower limit of normal (LLN) at the screening visit.
5. Have ferritin greater than/equal to the LLN, or total iron binding capacity (TIBC) less than/equal to ULN at the screening visit, based on central laboratory reference ranges. If a subject is receiving iron supplements at screening, the Investigator must ensure that the subject’s dose has been stable for 4 weeks prior to screening, and it must be maintained throughout the study. Subjects not receiving iron at screening must not start iron supplementation during the course of the study.
6. Body mass index (BMI) ≤ 35 kg/m2 at the screening visit.
7. Have a platelet count of >50,000/mm3 at the screening visit.
8. Have an absolute neutrophil count >500/mm3 at the screening visit.
9. Women of child-bearing potential (WOCBP) must have a negative pregnancy test at screening and must agree to use protocol-defined methods of contraception for the duration of the study and for 90 days after their last dose of study drug.
10. Males must agree to use protocol-defined methods of contraception and agree to refrain from donating sperm for the duration of the study and for 90 days after their last dose of study drug.
11. Have vaccination against Streptococcus pneumoniae, Neisseria meningitides (types A, C, W, Y, and B), and Haemophilus influenzae (type B) either within 2 years prior to Day 1 dosing, or agree to receive vaccination 14 days after starting treatment with APL-2 (along with prophylactic antibiotic therapy for at least the 14 days between APL-2 treatment initiation and vaccination and for 14 days post vaccination). Vaccination is mandatory, unless documented evidence exists that subjects are non-responders to vaccination (as evidenced by titers or display titer levels within acceptable local limits).
12. Be willing and able to give informed consent.

E.4

Principal exclusion criteria

Subjects will be excluded from the study if there is evidence of any of the following criteria at screening:
1. Treatment with any complement inhibitor (eg, eculizumab) within 3 months prior to screening.
2. Hereditary complement deficiency.
3. History of bone marrow transplantation.
4. Concomitant use of any of the following medications is prohibited if not on a stable regimen for the time period indicated below prior to screening:
• Erythropoietin or immunosuppressants for at least 8 weeks
• Systemic corticosteroids for at least 4 weeks
• Vitamin K antagonists (eg, warfarin) with a stable international normalized ratio (INR) for at least 4 weeks
• Iron supplements, vitamin B12, or folic acid for at least 4 weeks
• Low-molecular-weight heparin for at least 4 weeks
5. History or presence of hypersensitivity or idiosyncratic reaction to compounds related to the investigational product or SC administration.
6. Participation in any other investigational drug trial or exposure to other investigational agent, device, or procedure within 30 days or 5 half-lives, whichever is longer.
7. Planning to become pregnant or currently a breast-feeding woman.
8. History of meningococcal disease.
9. Any comorbidity or condition (such as malignancy) that, in the opinion of the Investigator, could put the subject at increased risk or potentially confound study data.

E.5 End points

E.5.1

Primary end point(s)

Hemoglobin stabilization defined as avoidance of a > 1 g/dl decrease in Hb levels from Baseline in the absence of transfusion through Week 26 (Yes/No)
AND
Reduction in lactate dehydrogenase (LDH) level from Baseline to Week 26

E.5.1.1

Timepoint(s) of evaluation of this end point

from Baseline through Week 26

E.5.2

Secondary end point(s)

Efficacy end points:
o Hemoglobin response (Yes/No) in the absence of transfusions (Hb response is defined as a ≥1g/dL increase in Hb from Baseline at Week 26)
o Change from Baseline to Week 26 in absolute reticulocyte count
o Change from Baseline to Week 26 in Hb level
o Number of packed red blood cell (PRBC) units transfused from Baseline to Week 26
o Change from Baseline to Week 26 in Functional Assessment of Chronic Illness Therapy- (FACIT-) Fatigue Scale score
o Normalization of Hb levels (defined as ≥1x ULN) from Baseline at Week 26 in the absence of transfusions (Yes/No)
o Normalization of LDH levels of ≤1 x the upper limit of normal (ULN) from Week 4 to Week 26 in the absence of transfusions (Yes/No)
o Change from Baseline to Week 26 in European Organization for Research and Treatment of Cancer (EORTC) 30-item Core Quality of Life Questionnaire (QLQ C30) scores (Version 3)
o Change from Baseline to Week 26 in Linear Analog Assessment (LASA) scale scores
o Change from Baseline to Week 26 in LDH level
o Absolute reticulocyte count normalization (<1 x ULN) at Week 26 (Yes/No)
o Time of failure of Hb stabilization
o Time to transfusion

Safety end points:
o Incidence and severity of treatment-emergent adverse events (TEAEs)
o Incidence of thromboembolic events
o Changes from Baseline in laboratory parameters
o Changes from Baseline in ECG parameters
o Incidence of anti-APL2 antibodies

E.5.2.1

Timepoint(s) of evaluation of this end point

from Baseline to Week 26

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Standard of Care (Excluding Complement Inhibitors)

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Argentina

Brazil

Colombia

Hong Kong

Hungary

Malaysia

Mexico

Peru

Philippines

Poland

Serbia

Thailand

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Following the completion of the Randomized-Controlled Period, subjects may be offered entry into a separate open-label, long-term extension study in order to continue to receive treatment with APL-2.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2019-07-23

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-05-16

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2021-06-23

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