Clinical Trials Register

Summary
EudraCT Number:	2013-002984-24
Sponsor's Protocol Code Number:	PHS-Px-104-II-01
National Competent Authority:	Austria - BASG
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2013-07-31
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

Austria - BASG

A.2

EudraCT number

2013-002984-24

A.3

Full title of the trial

A Safety Pilot Study of Px-104 in non alcoholic fatty liver disease (NAFLD) patients

Pilotstudie zur Untersuchung der Sicherheit von Px-104 in Patienten mit nichtalkoholischer Fettlebererkrankung

A.3.1

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

Safety Study of Px-104 in Patients with liver disease

Studie zur Untersuchung der Sicherheit von Px-104 in Patienten mit Lebererkrankung

A.4.1

Sponsor's protocol code number

PHS-Px-104-II-01

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	Phenex Pharmaceuticals AG
B.1.3.4	Country	Germany
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	Phenex Pharmaceuticals AG
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Koordinationszentrum für Klinische Studien
B.5.2	Functional name of contact point	CRO
B.5.3	Address:
B.5.3.1	Street Address	Kinderspitalgasse 15
B.5.3.2	Town/ city	Wien
B.5.3.3	Post code	A-1090
B.5.3.4	Country	Austria
B.5.4	Telephone number	+4414016025178
B.5.6	E-mail	michael.demel@meduniwien.ac.at

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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.2	Product code	Px-104
D.3.4	Pharmaceutical form	Capsule
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
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

Non-alcoholic fatty liver disease (NAFLD)

Nichtalkoholische Fettlebererkrankung

E.1.1.1

Medical condition in easily understood language

Liver disease

Fettleber

E.1.1.2

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	16.1
E.1.2	Level	PT
E.1.2	Classification code	10024670
E.1.2	Term	Liver disorder
E.1.2	System Organ Class	10019805 - Hepatobiliary disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Safety and tolerability assessment will be made by monitoring the subjects for adverse events and by interpreting the results of the ECGs, various laboratory tests (changes in ALT/AST) and the subjects’ diaries.

E.2.2

Secondary objectives of the trial

• Measurements of the hepatocellular lipid content (HCL)/composition and phosphorus metabolites by 3.0 and 7.0 Tesla Magnetic Resonance Spectroscopy (MRS) at 1H-MRS and 31P-MRS to investigate a lowering effect on HCL and possible changes in the liver cell metabolism. Comparison day 28 to baseline.
• Changes in oral glucose tolerance test (oGTT) using levels of glucose, insulin and c-peptide, FGF-19, GLP-1, DPP-4 as well as different measures of whole body insulin resistance (e.g. CLIX: serum creatinine, Gluc, C-Peptide) will be investigated prior and after administration of the study drug.
• Decrease of transaminases and parameters of cholestasis (ALT, AST, GGT, AP, Bilirubin)
• Potentially lowering of free serum cholesterol and triglycerols
• Reduction of body weight, BMI, waist-to-hip-ratio (WHR), ABSI (A body shape index)
• Plasma cholesterol lowering;
• FGF-19, Total bile acids reduction,

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Male or females
• Age 18-70 years
• Diagnosis of NAFLD as defined as (all of the following 5 points must apply):
1. NAFLD on liver biopsy within 2 years prior to study participation OR liver steatosis on any imaging (ultrasound, MRI, CT)
2. Disturbed metabolic homeostasis based on impaired HOMA-IR > 1
3. ALT within or above the upper tertial of the ULN (ALT < 45 for males, < 35 for females U/l) and/or GGT above ULN (GGT < 55 for males, < 38 for females U/l)
4. Steatosis > 15% at CAP Fibroscan at screening
5. Steatosis > 10% equivalent to histology at 1H-MRS at baseline
• Weight > 65 kg
• BMI > 25 and < 40
• Negative blood or urine pregnancy test (for females of childbearing potential) collected at screening followed by another negative serum pregnancy test collected within 24 hours prior to the first dose of study drug.
• Female patients must be postmenopausal, surgically sterile, or if premenopausal, must be prepared to use at least two effective (≤1% failure rate) method of contraception during the course of the study and for 14 days after the end of dosing. Male patients with female partners of child bearing potential must be prepared to use at least two effective methods of contraception with all sexual partners unless they have had a prior vasectomy. Effective methods of contraception are considered to be:
 Condom (male or female)
 Diaphragm, with spermicide
 Hormonal (e.g. contraceptive pill, patch, intramuscular implant or injection)
 Intrauterine device (IUD)
 Vasectomy (partner)
• Must be willing and able to give written informed consent and agree to comply with the study protocol.
• Sinus rhythm in 12-lead ECG

E.4

Principal exclusion criteria

• Evidence of excessive alcohol, drug or substance abuse
• History or other evidence of a medical condition associated with chronic liver disease other than NAFLD
• History or other evidence of decompensated liver disease (Child-Pugh Grade B or higher), coagulopathy, hyperbilirubinemia, hepatic encephalopathy, hypoalbuminemia, ascites, hepatic encephalopathy, and bleeding from esophageal varices are conditions consistent with decompensated liver disease.
• Concomitant intake of fibrates or statins
I. History of any structural cardiac disease requiring treatment:
• Any signs or symptoms of heart failure (NYHA II-IV)
• History of ventricular tachyarrhythmia requiring ongoing treatment
• History of bradyarrhythmia requiring Pacemaker treatment
• Relevant coronary artery disease
o History of myocardial infarction
o stable or unstable angina
II. Any clinically relevant findings in ECG at screening:
• Conduction abnormalities
o AV-Block 2nd (Type II) or 3rd degree
o Pauses > 3seconds
• Ventricular arrhythmia
o Monomorphic or polymorphic ventricular ectopic beats ≥ 30 beats/ hours calculated as mean over the continuous ECG recording period.
o Non-sustained ventricular tachycardia (three or more consecutive ventricular beats at a rate of greater than 100 beats/min)
• Atrial arrhythmia
o Atrial ectopic beats ≥ 30 beats/ hours calculated as mean over the continuous ECG recording period.
o Re-entrant supraventricular tachycardia
• Any type of tachycardia at rest (frequency >120/min at rest) in 12-lead ECG
• Sinus bradycardia <40 bpm as minimum recorded heart rate in 12-lead ECG or bradycardia <35 bpm in 24h Holter ECG
• Prolongation of QTc interval (QTc interval > 440 ms for male subjects or > 480 ms for female subjects) of >10% over 24 hours using the Fridericia method for QTc analysis.
IIII. Poorly controlled hypertension, OR (2) screening or baseline blood pressure ≥ 160 mmHg for systolic OR (3) screening or baseline blood pressure ≥ 100 mmHg for diastolic blood pressure.
IV. History of cerebrovascular disease:
• History of any stroke or transient ischemic attack
• Type I or II diabetes with HbA1C > 6.5% at screening and/or fasting plasma glucose > 7mmol/L (> 126 mg/dl).
• History or other evidence of a clinically relevant ophthalmologic disorder due to diabetes mellitus or hypertension or history or other evidence of severe retinopathy
• Known sensibility to any ingredients contained in the IMP
• All conditions that do not allow MR assessments
• History of having received any investigational drug ≤ 3 months and/or 6 x half-life prior to the first dose of study drug or the expectation that such drugs will be used during the study. Patients enrolled in this study cannot be enrolled in another study for either research, diagnostic or treatment purposes.
• Woman with childbearing potential unless using adequate contraception; females who are pregnant or breast feeding.
• History of severe allergic or immunologically mediated disease [(e.g., vasculitis, cryoglobulinemia, inflammatory bowel disease, idiopathic thrombocytopenic purpura, lupus erythematosus, autoimmune hemolytic anemia, scleroderma, severe psoriasis (defined as affecting > 10% of the body, where the palm of one hand equals 1%, or if the hands and feet are affected), rheumatoid arthritis requiring more than intermittent nonsteroidal anti-inflammatory medications for management, etc.]
• Evidence of an active or suspected cancer, or a history of malignancy within the last 2 years, with the exception of patients with basal cell carcinoma that has been excised and cured.
• History of any systemic anti-neoplastic or immunomodulatory treatment (including supraphysiologic doses of steroids and radiation) 6 months prior to the first dose of study drug or the expectation that such treatment will be needed at any time during the study.
• History of bleeding disorders or anticoagulant use
• History or other evidence of chronic pulmonary disease associated with functional limitation.
• History of uncontrolled severe seizure disorder.
• Poorly controlled thyroid dysfunction.
• History of major organ transplantation with an existing functional graft.
• Any signs of acute infection or inflammation
• History or other evidence of severe illness, or any other conditions which would make the patient, in the opinion of the investigator, unsuitable for the study.
• Any herbal supplements containing silymarin, tocopherol, vitamin C, bioflavins, curcumin. (at least 4-6 months before the study)
• Positive test at screening for anti-HAV IgM Ab, HBsAg, anti-HBc IgM Ab, or anti-HIV Ab.
• Subjects who have undergone surgery within the last 3 months.
• Subjects who have had a prior gastrointestinal surgery.
• Subjects who will be unavailable for the duration of the trial, who are unlikely to be compliant with the protocol, or who are felt to b unsuitable by the investigator for any other reason
• Imprisonment

E.5 End points

E.5.1

Primary end point(s)

Safety Endpoints:
• Number of AEs, SAEs, TEAE
• Changes in vital signs from baseline
• ECG-related safety endpoints:
o Occurrence of VES (determined by Holter-ECG)
o Change of QTc (derived from 12-lead ECG) from baseline
• Hepatological safety endpoints:
o Change of ALT, AST from baseline
o Change of Bilirubin from baseline
• Changes in other laboratory values (e.g. serum creatinine) from baseline
• Changes in concomitant medication

E.5.1.1

Timepoint(s) of evaluation of this end point

28 days post-baseline

E.5.2

Secondary end point(s)

Change in of hepatocellular lipid content (HCL; derived using MRS) from baseline to Day 28.
• Changes in glucose, insulin and C-peptid concentrations (derived using oral glucose tolerance test (oGTT)) from baseline to Day 28.
• Change in levels of transaminases and parameters of cholestasis (ALT, AST, GGT, AP, Bilirubin) from baseline
• Lowering of free serum cholesterol and triglycerides from baseline
• Changes in bile acid composition and lowering of total plasma bile acid pool from baseline
• Reduction of body weight, BMI, waist-to-hip-ratio (WHR), ABSI (A body shape index) baseline
• Changes in phagocytic function of Kupffer cells (KCs) and possible microcirculatory changes in the liver from baseline. Changes in other serum or plasma markers of liver inflammation and fibrotisation (CK-18, sCD163, Procollagen III peptide, Hyaluronic Acid, TIMP-1, alpha2-macroglobulin, haptoglobin, HRG-1 and others) from baseline
• Changes in bacterial translocation as evidenced by SLM-S test from baseline

E.5.2.1

Timepoint(s) of evaluation of this end point

28 days post-baseline

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

E.6.7

Pharmacodynamic

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

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

Yes

E.8.1.7.1

Other trial design description

Single-arm, Pilot study

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

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

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

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

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.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.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)

No special post trial treatment is anticipated. After trial completion study participants will be treated according to standrad-of-care.

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2013-10-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-07-30

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2015-01-19

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