Clinical Trials Register

Summary
EudraCT Number:	2015-001625-16
Sponsor's Protocol Code Number:	PBI-4050-ATX-9-05
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:	2015-09-01
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

2015-001625-16

A.3

Full title of the trial

A Phase 2, Single-Arm, Open-Label Study to Evaluate the Safety and Tolerability of PBI-4050 and of its Effects on the Inflammatory, Fibrosis,Diabetes and Obesity Biomarkers in Subjects with Alström Syndrome

A.3.1

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

A study to investigate the safety and the effects of PBI-4050 when given to
patients with the rare genetic disorder, Alström Syndrome

A.3.2

Name or abbreviated title of the trial where available

Phase II Study of PBI-4050 in Subjects with Alström Syndrome

A.4.1

Sponsor's protocol code number

PBI-4050-ATX-9-05

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	ProMetic BioSciences Inc.
B.1.3.4	Country	Canada
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	ProMetic BioSciences Inc.
B.4.2	Country	Canada
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	ProMetic Biosciences Inc.
B.5.2	Functional name of contact point	Tanya Palmer
B.5.3	Address:
B.5.3.1	Street Address	Horizon Park, Barton Road, Comberton
B.5.3.2	Town/ city	Cambridge
B.5.3.3	Post code	CB23 7AJ
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	01280848511
B.5.6	E-mail	tanya.palmer@theccl.co.uk

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	PBI-4050
D.3.4	Pharmaceutical form	Capsule, soft
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	3-pentylbenzeneacetic acid sodium salt
D.3.9.1	CAS number	1254472-97-3
D.3.9.2	Current sponsor code	PBI-4050
D.3.9.4	EV Substance Code	AS1
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	200
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

Alström Syndrome

E.1.1.1

Medical condition in easily understood language

A rare genetic disorder caused by mutations in the gene ALMS1

E.1.1.2

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.1
E.1.2	Level	LLT
E.1.2	Classification code	10068814
E.1.2	Term	Alstrom syndrome
E.1.2	System Organ Class	100000004850

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 safety and tolerability of 800mg PBI-4050 (the Investigational Medicinal Product), administered orally once daily for 24 weeks, in subjects with Alström Syndrome.

E.2.2

Secondary objectives of the trial

The secondary objectives are:
- To evaluate the effect of the IMP (PBI-4050) on metabolic syndrome
parameters
- To evaluate the effect of the IMP on pro-inflammatory/inflammatory,
fibrotic, diabetic, and obesity biomarkers in blood and urine
- To evaluate the effect of the IMP on anti diabetic treatment, including
oral therapy and insulin requirements.
The exploratory objectives are:
- To examine the effect of the IMP on the histological appearances seen
in fat biopsies, in particular the degree of fibrosis and macrophage
infiltration.
- To analyse the effect of the IMP on global metabolome (smallmolecule
chemicals found within a biological sample) using the systemic
blood samples and adipose tissue-specific micro dialysis samples.
- To analyse the effect of the IMP on the microdialysate fractions using
the adipose tissue micro dialysis samples.
- To assess the effect of the IMP on liver stiffness using the FibroScan
- To measure the effect of the IMP on the fat content

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Subject is 16 years of age or older at screening.
2. Subject has signed informed consent.
3. Subject has a documented diagnosis of Alström syndrome, confirmed by genetic testing before screening.
4. Subject on diabetes treatment has been receiving the same antidiabetic agent(s) for a minimum of 1 month before screening.
5. Subject is able and willing to self-monitor blood glucose level at home or can obtain adequate assistance from care givers.
6. Female subjects of childbearing potential who are sexually active with a nonsterile male partner must have a negative serum or urine pregnancy test at screening and agree to use adequate birth control from screening throughout the study and for 30 days after the last IMP administration.
If a male subject has not been vasectomized at least 6 months before screening and partners with a woman of childbearing potential, he must be willing to use an acceptable contraceptive method throughout the study and for 30 days after the last IMP administration.
Explanatory note: A female subject is considered to be of childbearing potential unless she has had a hysterectomy, is at least one year post-menopausal, or has undergone tubal ligation. Adequate birth control includes at least one medically approved and highly effective method of birth control, defined as those which result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly, such as implants, injectables, oral contraceptives combined with at least one barrier method.
Acceptable contraceptive methods for a male subject include simultaneous use of condoms and, for his female partner, the use of hormonal contraceptives, intra-uterine contraceptive device, or diaphragm with intravaginally applied spermicide. Only male subjects whose vasectomy has been confirmed by semen analysis at least 3 months after the vasectomy are allowed not to use acceptable contraceptive methods.

E.4

Principal exclusion criteria

1. Subject has recent or on-going infection requiring systemic treatment with an anti-infective agent within 30 days before screening.
2. Subject has had at least two documented episodes of severe hypoglycaemia within 12 months before screening. Severe hypoglycaemia is defined as an episode of confirmed hypoglycaemia (glucose < 3.0 mmol/L) that required parenteral treatment with intramuscular injection of glucagon or intravenous injection of dextrose, an episode of confirmed hypoglycaemia that did not require parenteral treatment but involved severe neuroglycopenic symptoms, or an episode of unconfirmed hypoglycaemia that resulted in seizure or coma.
3. Subject has uncontrolled hypertension with BP > 170/100 mmHg as determined at screening.
4. Subject has alanine transaminase (ALT) or aspartate transaminase (AST) level ≥ 5 × upper limit of normal (ULN) at screening.
5. Subject is currently using weight loss medications at screening. Subjects may be re-screened after stopping the weight loss medication for a period of at least 5 half-lives.
6. Subject has used any moderate/potent inducer or inhibitor of CYP2C9 isozyme or any strong inducer or inhibitor of cytochrome P450 (CYP) 3A isozyme within 30 days prior to the first study drug administration.
7. Subject has a history of chronic alcohol or other substance abuse as determined at screening.
8. Woman who is pregnant, breast-feeding, or planning a pregnancy during the course of the study as determined at screening.
9. Subject has any condition that, in the investigator’s opinion, is likely to interfere with study conduct and compliance.
10. Subject has a history of an allergic reaction to PBI-4050 or any of its excipients.

E.5 End points

E.5.1

Primary end point(s)

Safety:
• AEs
• AEs of special interest: incidence of hypoglycaemia (despite adequate adjustment of other antidiabetic concomitant medication):
o Suspected symptomatic hypoglycaemia: Symptoms of hypoglycaemia (shaking, dizziness, blurred vision, palpitations, sweating, etc.) with no confirmatory blood glucose level, or blood glucose 3.5 – 3.9 mmol/L with or without symptoms
o Confirmed hypoglycaemia: Blood glucose <3.5 mmol/L with or without symptoms (shaking, dizziness, blurred vision, palpitations, sweating, etc.)
o Severe hypoglycaemia events: Blood glucose < 3.0 mmol/L and/or loss of consciousness.

E.5.1.1

Timepoint(s) of evaluation of this end point

Assessments during study visits at weeks 4, 8, 12, 16, 20, 24, EP12, EP24, EP36, EP48, and 30 days after final dose.

E.5.2

Secondary end point(s)

Efficacy:
• Changes from baseline in metabolic syndrome parameters:
o Fasting plasma glucose
o Haemoglobin A1c (HbA1c)
o Fasting insulin
o Homeostasis Model Assessment for steady state beta cell function (HOMA-B) and insulin sensitivity (HOMA-S)
• Changes from baseline in pro-inflammatory/ inflammatory, fibrotic, diabetic, and obesity markers:
o Blood: interferon gamma (IFNγ), cystatin C, interleukin 6 (IL-6), IL-8, monocyte chemoattractant protein 1 (MCP-1), tumour necrosis factor alpha (TNFα), IL-10, high-specificity C-reactive protein (hsCRP), vascular endothelial growth factor (VEGF), adiponectin, glucagon
o Urine: albumin/creatinine ratio (ACR, in mg/mmol), MCP-1
• Change from baseline in cardiac function parameter: NT proBNP
• Changes from baseline in antidiabetic medications, including oral and insulin therapies and dosages.

E.5.2.1

Timepoint(s) of evaluation of this end point

Assessments during study visits at weeks 4, 8, 12, 16, 20, 24, EP12, EP24, EP36, EP48, and 30 days after final dose.

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

Yes

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

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.8.3

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

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

Yes

F.1.1