Clinical Trials Register

Summary
EudraCT Number:	2018-000966-12
Sponsor's Protocol Code Number:	EL-004
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2019-06-25
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

Germany - BfArM

A.2

EudraCT number

2018-000966-12

A.3

Full title of the trial

A Phase 2 Open Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Dose Levels of Subcutaneously Administered ELX-02 in Patients with Cystic Fibrosis with at Least One G542X Allele

A.3.1

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

A Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Dose Levels of Subcutaneously Administered ELX-02 in Patients with Cystic Fibrosis

A.4.1

Sponsor's protocol code number

EL-004

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	Eloxx 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	Eloxx 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	Eloxx Pharmaceuticals, Inc.
B.5.2	Functional name of contact point	Tim Kachmar
B.5.3	Address:
B.5.3.1	Street Address	480 Arsenal Way, Suite 130
B.5.3.2	Town/ city	Watertown, MA
B.5.3.3	Post code	02472
B.5.3.4	Country	United States
B.5.4	Telephone number	+16176459926
B.5.6	E-mail	tim.kachmar@eloxxpharma.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/3/18/2072
D.3 Description of the IMP
D.3.2	Product code	ELX-02
D.3.4	Pharmaceutical form	Lyophilisate for solution for injection
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	Not Assigned
D.3.9.1	CAS number	1375073-94-1
D.3.9.2	Current sponsor code	ELX-02
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	160
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	Yes
D.2.1.1.1	Trade name	Kalydeco
D.2.1.1.2	Name of the Marketing Authorisation holder	Vertex Pharmaceuticals (Ireland) Limited
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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/3/08/556
D.3 Description of the IMP
D.3.1	Product name	Kalydeco
D.3.4	Pharmaceutical form	Film-coated 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	Ivacaftor
D.3.9.1	CAS number	873054-44-5
D.3.9.4	EV Substance Code	SUB33103
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	150
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

Cystic fibrosis (CF)

E.1.1.1

Medical condition in easily understood language

Inherited conditions caused by nonsense mutations

E.1.1.2

Therapeutic area

Body processes [G] - Genetic Phenomena [G05]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10011762
E.1.2	Term	Cystic fibrosis
E.1.2	System Organ Class	10010331 - Congenital, familial and genetic disorders

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

1. To assess the safety and tolerability of different dose levels and exposures of ELX-02 administered subcutaneously (SC), as monotherapy and in combination with ivacaftor in patients with CF carrying at least one G542X CFTR or phenotypically similar nonsense allele.
2. To study the PK of multiple SC doses of ELX-02 as monotherapy and in combination with ivacaftor, in patients with CF.

E.2.2

Secondary objectives of the trial

1. To study the PD of multiple doses of ELX-02 as monotherapy and in combination with ivacaftor on sweat chloride concentration (SCC).
2. To study the PD of multiple doses of ELX-02 as monotherapy and in combination with ivacaftor on pulmonary function (forced expiratory volume [FEV], forced vital capacity [FVC], and forced expiratory flow at 25-75%] FEF).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Evidence of signed and dated informed consent/assent document(s) indicating that the subject (and/or his parent/legal guardian) has been informed of all pertinent aspects of the trial
2. Understands, and is willing and able to comply with all scheduled visits, treatment plan, laboratory tests, and other study procedures
3. Males and females age 18 years and above; in countries where permitted, males and females age 16 and above
4. A confirmed diagnosis of nmCF with a documented G542X or phenotypically similar nonsense mutation, homozygote, or compound heterozygote with one of the specified mutations. For heterozygotes, one mutation has to be a G542X or phenotypically similar nonsense mutation, and the second mutation should be any Class 1 or Class 2 mutation. Patients with one G542X or phenotypically similar nonsense allele and a second allele that is not in the above list may be potentially allowed but only after discussion on a case by case basis with and written approval from the Sponsor.
5. Documented SCC ≥ 60 mEq
6. FEV1 ≥ 40% predicted normal for age, gender and height at Screening (Knudson Equation)
7. Stable regimen of oral CF medications, inhaled antibiotics, dornase alfa, and hypertonic saline, and physiotherapy for the period 28 days prior to Screening
8. Non-smokers for at least 180 days (6 months) prior to Screening
9. Must be willing to abstain from strenuous exercise during the 24 hours prior study visits
10. Females of childbearing potential and males capable of fathering a child must meet the contraception requirements outlined in Section ‎6.4
11. Non-lactating females
12. Females on hormone replacement therapy (estrogen or progesterone) or contraceptive therapy must be stabilized on a product and dose for at least 30 days prior to Screening
13. Glomerular filtration rate (GFR) of > 60 mL/min/1.73m2 at Screening (GFR to be calculated using the Chronic Kidney Disease Epidemiology Collaboration CKD-EPI formula
14. Have not received systemic medications with potential to impair renal function on a frequent basis (e.g., non steroidal anti inflammatory drugs [NSAIDs]) or with ototoxic potential (e.g., quinine or salicylates), or any injectable aminoglycosides for a period of at least 14 days prior to dosing
15. Negative human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), and hepatitis C virus antigen (HCV Ag) serology tests at Screening
16. No history of alcohol or drug abuse within the 6 months prior to Screening
17. Body Mass Index (BMI) of 19.0 to 30.0 kg/m2 (inclusive). Patients with a lower BMI may be entered into the study at the discretion of the investigator following consultation with the Sponsor.

E.4

Principal exclusion criteria

1. Patients who are investigational site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the Investigator, or patients who are Eloxx Pharmaceuticals employees directly involved in the conduct of the study
2. Participation in clinical study including administration of any investigational drug or device in the last 30 days or 5 half-lives (whichever is longer) prior to investigational product dosing in the current study
3. Use of prohibited medications as defined in Section ‎6.1 within the specified windows
4. History of any comorbidity which in the opinion of the investigator might confound the study or pose an additional risk in administering the study drug to the patient
5. History of any organ transplantation
6. Liver disease characterized by cirrhosis or portal hypertension. Patients with alanine aminotransferase (ALT), aspartate aminotransferase (AST), and/or a total bilirubin 3.0 times the upper limit of normal (ULN) will be excluded
7. History of clinically significant adrenal disease needing hormone replacement therapy
8. History of congestive heart failure diagnosed clinically or with documented left ventricular ejection fraction (LVEF) ≤ 40%
9. Evidence or history of clinically relevant psychiatric condition
10. A positive urine drug screen (amphetamines, benzodiazepines, cocaine and opiates) at Screening
11. Screening supine 12-lead electrocardiogram (ECG) demonstrating any clinically significant findings as judged by the Investigator
12. Patients with any abnormalities in clinical laboratory tests at Screening, considered by the study physician as clinically relevant
13. Major surgery within 180 days (6 months) of Screening
14. Patients without documented prior aminoglycoside exposure who have a mitochondrial mutation that has been shown to increase sensitivity to aminoglycosides
15. Known allergy to any aminoglycoside
16. Patients with any acute medical situation not related to CF (e.g., gastroenteritis) unresolved within 14 days of first dose that is considered of significance by the Investigator
17. Patients with any abnormality at ENT screening, that indicates the presence of a vestibular toxicity associated with prior exposure to aminoglycosides.
18. Dizziness Handicap Inventory (DHI)-H score at screening >16.
19. Patients receiving CFTR modulators or potentiators as defined in Section ‎6.1 within 2 months of study enrollment
20. Patients unable to avoid foods or drinks that contain grapefruit or Seville oranges, as these may affect the amount of ivacaftor in the body. Patients who meet this exclusion criterion and have already started the study prior to Protocol Amendment 5.0 will not be allowed to proceed to Treatment Period 5
21. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption. Patients who meet this exclusion criterion and have already started the study prior to Protocol Amendment 5.0 will not be allowed to proceed to Treatment Period 5

E.5 End points

E.5.1

Primary end point(s)

Primary Endpoints:
1. The incidence and characteristics of adverse events (AEs). Other safety assessments will include injection site reactions (DAIDS Grading Scale) and changes from baseline in vital signs, physical examination, electrocardiograms, blood and urine safety laboratory tests, audiometric testing (including high frequency audiometry) and Tinnitus Handicap Inventory (THI) and Dizziness Handicap Inventory (DHI) questionnaires.
2. Plasma and urine PK parameters of ELX-02 following the first dose and at steady state, at each dose level (Treatment Periods 1-5).
3. Plasma PK parameters of ivacaftor following the first dose and at steady state (Treatment Period 5)

E.5.1.1

Timepoint(s) of evaluation of this end point

1. From screening until End-of-Study (EOS) visit;

2.
Blood PK parameters: D1, D2, D7 of treatment periods 1-3, Day 14 of treatment period 4, End-of-Study (EOS) visit.
Urine PK parameters: D1, D2 of all treatment periods

E.5.2

Secondary end point(s)

Secondary Endpoints:
1. PD as assessed by changes from baseline in SCC following ELX-02 treatment
2. PD as assessed by changes from baseline in pulmonary function including FEV1, FVC, and FEF25-75, absolute values and percent predicted.
3. Dose and PK relationship.

E.5.2.1

Timepoint(s) of evaluation of this end point

During treatment

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

E.6.4

Safety

Yes

E.6.5

Efficacy

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

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

tolerability

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

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

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

Australia

Israel

Germany

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)

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)

see protocol

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

2019-10-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-11-18

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2022-04-05

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