Clinical Trials Register

Summary
EudraCT Number:	2016-002652-25
Sponsor's Protocol Code Number:	ACH471-100
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2017-10-27
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

UK - MHRA

A.2

EudraCT number

2016-002652-25

A.3

Full title of the trial

A Phase 2 Open-Label Proof of Concept Study to Assess the Efficacy, Safety, and Pharmacokinetics of ACH-0144471 in Untreated Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH)

A.3.1

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

A treatment study of ACH-0144471 in Untreated Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH)

A.4.1

Sponsor's protocol code number

ACH471-100

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03053102

A.5.3

WHO Universal Trial Reference Number (UTRN)

U1111-1190-3490

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	Achillion 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	Achillion 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	Achillion Pharmaceuticals, Inc.
B.5.2	Functional name of contact point	Clinical Operations
B.5.3	Address:
B.5.3.1	Street Address	300 George Street
B.5.3.2	Town/ city	New Haven
B.5.3.3	Post code	CT 06511
B.5.3.4	Country	United States
B.5.4	Telephone number	+1 203-752-5577
B.5.6	E-mail	PNHTrialInquiries@achillion.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/3/17/1946
D.3 Description of the IMP
D.3.2	Product code	ACH-0144471
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Not available
D.3.9.1	CAS number	1903768-17-1
D.3.9.2	Current sponsor code	ACH-0144471
D.3.9.3	Other descriptive name	ACH-0144471
D.3.9.4	EV Substance Code	SUB189885
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
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.IMP: 2
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/3/17/1946
D.3 Description of the IMP
D.3.2	Product code	ACH-0144471
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Not available
D.3.9.1	CAS number	1903768-17-1
D.3.9.2	Current sponsor code	ACH-0144471
D.3.9.3	Other descriptive name	ACH-0144471
D.3.9.4	EV Substance Code	SUB189885
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	75
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.IMP: 3
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/3/17/1946
D.3 Description of the IMP
D.3.2	Product code	ACH-0144471
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Not available
D.3.9.1	CAS number	1903768-17-1
D.3.9.2	Current sponsor code	ACH-0144471
D.3.9.3	Other descriptive name	ACH-0144471
D.3.9.4	EV Substance Code	SUB189885
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
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

Untreated Paroxysmal Nocturnal Hemoglobinuria (PNH)

E.1.1.1

Medical condition in easily understood language

Rare blood disorder that that causes red blood cells to break down earlier than they should

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

To evaluate the efficacy of 28 days of oral dosing with ACH-0144471 in currently untreated PNH patients, based on decreases in lactate dehydrogenase (LDH)

E.2.2

Secondary objectives of the trial

• To evaluate the efficacy of 28 and 84 days of oral dosing with ACH-0144471 in currently untreated PNH patients, based on increases in hemoglobin (Hgb) levels
• To evaluate the safety and tolerability of ACH-0144471 in currently untreated PNH patients receiving daily oral dosing by assessing SAEs, AEs ≥ Grade 3, and laboratory abnormalities ≥ Grade 3, and events leading to discontinuation of study drug
• To evaluate the pharmacokinetic (PK) and pharmacodynamics (PD) profile of ACH-0144471 in currently untreated PNH patients receiving daily oral dosing for 28 days

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Currently untreated PNH patients with PNH Type III erythrocyte and/or granulocyte clone size ≥10% and anemia (Hgb <12 g/dL) with adequate reticulocytosis (as determined by the investigator)
2. LDH ≥1.5× upper limit of normal (ULN)
3. Platelet count ≥50,000/μL without the need for platelet transfusions
4. Documentation of vaccination for N. meningitidis, H. influenzae, and S. pneumoniae, or willingness to receive vaccinations as described in Section 6.3
5. Age ≥18 years (or ≥ minimum adult age in accordance with local legal requirements)
6. Female participants of childbearing potential must agree to use an acceptable method of contraception (as defined in Section 5.5.5) from the date of signing the informed consent to the first day of dosing (Day 1), and must agree to use a highly effective method of contraception (as defined in Section 5.5.5) from the first day of dosing to 30 days after their last dose of study drug. Female participants of childbearing potential must also have a negative serum pregnancy test during Screening and negative urine pregnancy test on Day 1.
Female participants of non-childbearing potential need not employ a method of contraception.
7. Non-sterile male participants must agree to use a highly effective method of contraception (as defined in Section 5.5.5) with their partner(s) of childbearing potential from the first day of dosing to 90 days after their last dose of study drug.
Males who are surgically sterile need not employ additional contraception.
Males must agree not to donate sperm while enrolled in this study and for 90 days after their last dose of study drug.
8. Must agree to provide written informed consent
9. Must be willing, at all times, to have transportation and telephone access, and to be within one hour of an emergency medical center

E.4

Principal exclusion criteria

1. History of a major organ transplant (e.g., heart, lung, kidney, liver) or hematopoietic stem cell/marrow transplant
2. History of dosing with another investigational agent within 30 days or 5 half-lives of the investigational agent prior to study drug administration, whichever is greater
3. History of dosing with eculizumab at any dose or interval within the past 75 days before study drug administration
4. Known or suspected complement deficiency
5. Contraindication to one or more of the required vaccinations
6. Active bacterial infection or clinically significant active viral infection, a body temperature >38°C, or other evidence of infection on Day 1, or history of febrile illness within 14 days prior to first study drug administration
7. History of meningococcal infection, or a first-degree relative or household contact with a history of meningococcal infection
8. History of hypersensitivity reactions to commonly used antibacterial agents, including beta-lactams, penicillin, aminopenicillins, fluoroquinolones (specifically including ciprofloxacin), cephalosporins, and carbapenems, which in the opinion of the investigator would make it difficult to properly provide either empiric antibiotic therapy or treat an active infection
9. History or presence of any clinically relevant co-morbidities that would make the patient inappropriate for the study (for example, is likely to result in deterioration of the patient’s condition, affect the patient’s safety during the study, or confound the results of the study)
10. Laboratory abnormalities at screening, including:
• Alkaline phosphatase (ALP) >1.5× upper limit of normal (ULN)
• Absolute neutrophil count (ANC) <1,000/μL
• Alanine aminotransferase (ALT) > ULN
• Any other clinically significant laboratory abnormality that, in the opinion of the Primary Investigator (PI), would make the patient inappropriate for the study or put the patient at undue risk
11. Females who are pregnant, nursing, or planning to become pregnant during the study or within 90 days of study drug administration or patients with a female partner who is pregnant, nursing, or planning to become pregnant during the study or within 90 days of study drug administration
12. Prior history or current evidence of biliary cholestasis
13. Gilbert’s syndrome
Patients with history or family history suggestive of Gilbert’s syndrome should be tested and excluded from study if positive for UGT1A1 genotyping polymorphism or missense change
14. Evidence of human immunodeficiency virus (HIV), hepatitis B or hepatitis C infection (positive serology for HIV-1 antibody (HIV Ab), positive hepatitis B surface antigen (HbsAg), or positive anti-HCV antibody (HCV Ab) at Screening or historically)

E.5 End points

E.5.1

Primary end point(s)

Relative decrease in LDH from baseline

E.5.1.1

Timepoint(s) of evaluation of this end point

Day 28

E.5.2

Secondary end point(s)

• To evaluate the efficacy of oral dosing with ACH-0144471 in currently untreated PNH patients, based on increases in hemoglobin (Hgb) levels
• To evaluate the safety and tolerability of ACH-0144471 in currently untreated PNH patients receiving daily oral dosing by assessing SAEs, AEs ≥ Grade 3, and laboratory abnormalities ≥ Grade 3, and events leading to discontinuation of study drug
• To evaluate the pharmacokinetic (PK) and pharmacodynamics (PD) profile of ACH-0144471 in currently untreated PNH patients

E.5.2.1

Timepoint(s) of evaluation of this end point

• To evaluate the efficacy of oral dosing with ACH-0144471 in currently untreated PNH patients, based on increases in hemoglobin (Hgb) levels (Day 28 and Day 84)
• To evaluate the safety and tolerability of ACH-0144471 in currently untreated PNH patients receiving daily oral dosing by assessing SAEs, AEs ≥ Grade 3, and laboratory abnormalities ≥ Grade 3, and events leading to discontinuation of study drug (up to 15 weeks)
• To evaluate the pharmacokinetic (PK) and pharmacodynamics (PD) profile of ACH-0144471 in currently untreated PNH patients (up to Day 28)

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

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Assessment of Biomarkers

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

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

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the 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

Italy

Korea, Republic of

New Zealand

United Kingdom

E.8.7

Trial has a data monitoring committee

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 Day 84 to Day 104 (6-day taper + 14 day follow up).
The sponsor reserves the right to close any study site or terminate the study at any time for any reason at the sole discretion of the sponsor.

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

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)

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)

After the patient has finished the trial, they will have the option to participate in a long-term-treatment study with ACH-0144471 (Patients may remain in that study until ACH-0144471 is commercially available in their country or the development of ACH-0144471 as a potential therapy for PNH is terminated, or until the therapy is no longer tolerated or effective). Sponsor reserves the right to close any study site or terminate the study at any time for any reason (sole discretion of the sponsor).

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

2017-12-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-02-02

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-02-27

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