Clinical Trials Register

Summary
EudraCT Number:	2014-000350-11
Sponsor's Protocol Code Number:	2032/MUL
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:	2014-03-10
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

2014-000350-11

A.3

Full title of the trial

An open label, randomized study to investigate the safety of weekly pentosan polysulfate injections in adult patients with Mucopolysaccharidosis Type I receiving enzyme replacement therapy.

Eine offene, randomisierte Studie zur Untersuchung der Sicherheit von wöchentlichen Pentosanpolysulfatinjektionen bei erwachsenen Patienten mit Mukopolysaccharidose Typ I, die eine Enzymersatztherapie erhalten.

A.3.1

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

Treatment of patients, who have Mucopolysaccharidosis Type I, receiving pentosan polysulfate subcutaneous injections weekly

Behandlung von Patienten, die an Mukopolysaccharidose Typ I erkrankt sind, mit einer wöchentlichen Injektion Pentosanpolysulfat

A.4.1

Sponsor's protocol code number

2032/MUL

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	Multiplex Pharma Holdings LLC
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	Multiplex Pharma Holdings LLC
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	bene pharmaChem GmbH & Co. KG
B.5.2	Functional name of contact point	Klaus Maag, MD
B.5.3	Address:
B.5.3.1	Street Address	Bayerwaldstr. 7-9
B.5.3.2	Town/ city	Geretsried
B.5.3.3	Post code	82538
B.5.3.4	Country	Germany
B.5.4	Telephone number	+4981719825302
B.5.5	Fax number	+4981719825350
B.5.6	E-mail	k.maag@bene-pharmachem.de

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	Yes
D.2.1.1.1	Trade name	Pentosan Polysulfat SP 54® injection solution
D.2.1.1.2	Name of the Marketing Authorisation holder	bene-Arzneimittel GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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.3.1	Product name	Pentosan Polysulphate SP54®
D.3.4	Pharmaceutical form	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	PENTOSAN POLYSULFATE SODIUM
D.3.9.1	CAS number	37319-17-8
D.3.9.3	Other descriptive name	Pentosan Polysulphate SP54
D.3.9.4	EV Substance Code	SUB14801MIG
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	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
D.3.11.13.1	Other medicinal product type	Pentosan polysulfate sodium (PPS), is a polysaccharide extracted from beech wood and esterified with sulphuric acid. PPS belongs to the polyanions having high electric chargedensity.

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

Mucopolysaccharidosis type I (alpha-L-Iduronidase deficiency)

E.1.1.1

Medical condition in easily understood language

Mucopolysaccharidosis type I (absence/insufficient levels of the enzyme alpha-L-iduronidase)

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	17.0
E.1.2	Level	LLT
E.1.2	Classification code	10056888
E.1.2	Term	Mucopolysaccharidosis IS
E.1.2	System Organ Class	100000004850

E.1.2 Medical condition or disease under investigation

E.1.2	Version	17.0
E.1.2	Level	LLT
E.1.2	Classification code	10056887
E.1.2	Term	Mucopolysaccharidosis IH/S
E.1.2	System Organ Class	100000004850

E.1.2 Medical condition or disease under investigation

E.1.2	Version	17.0
E.1.2	Level	LLT
E.1.2	Classification code	10028094
E.1.2	Term	Mucopolysaccharidosis IH
E.1.2	System Organ Class	100000004850

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To establish the safety of weekly subcutaneous injections of 1 mg/kg and 2 mg/kg body weight Pentosan Polysulphate SP54® in the treatment of Mucopolysaccharidosis Type I.

E.2.2

Secondary objectives of the trial

To investigate the effect of pentosan polysulfate (PPS) on:
- 6 minute walk test
- pulmonary function
- grip test
- quality of life
- pain intensity
- range of motion
- inflammatory biomarkers
- glycosaminoglycan (GAG)
- CRP (C-reactive protein) and ESR (erythrocyte sedimentation rate)
- measurement of pentosan polysulfate

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or female.
2. Age ≥18 years.
3.Diagnosed as having Mucopolysaccharidosis Type I (alpha-L-Iduronidase deficiency) and have been treated with enzyme replacement therapy (ERT) for a minimum of 24 months.
4. Joint pain and/or reduced joint range of motion at time of enrolment according to the investigator.
5. Written informed consent upon enrolment.

E.4

Principal exclusion criteria

1. History of hypersensitivity to pentosan polysulfate or any of the excipients.
2. Known allergic reaction to heparin or pentosan polysulfate e.g. heparin induced thrombocytopenia.
3. Clinically relevant concomitant severe condition (with the exception of signs and symptoms relating to MPSI) e.g. gastrointestinal (including gastrointestinal ulcerations, polyps, or diverticula), renal, hepatic (ALT and/or AST >10 times upper limit of reference range), pancreatic, pulmonary, cardiovascular (including endocarditis lenta), aneurysm, cerebral hemorrhage, hematological (including thrombocytopenia, hemophilia, hemorrhagic diathesis), endocrinological, suspected tumors with risk of bleeding, neurological, or psychiatric conditions in the opinion of the investigator.
4. Planned invasive procedure other than blood sampling.
5. History of or planned bone marrow transplant.
6. Clinically relevant abnormal laboratory test results including liver enzymes, thrombocytopenia, prolonged clotting time.
7. Intake of anti-inflammatory agents e.g. corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) other than ibuprofen or paracetamol within 10 half lives (t½) of the drug prior to first dosing and throughout the study.
8. Intake of anti-thrombotic agents e.g. heparin, tissue plasminogen activator (t-PA), streptokinase, aspirin within 10 half lives (t½) of the drug prior to first dosing and throughout the study. Coumarin anticoagulants are permitted.
9. Known history or presence of alcohol or substance abuse.
10. Known hepatitis B or C or human immunodeficiency virus (HIV) or syphilis seropositivity. Note: testing for hepatitis and HIV will be performed as part of the screening procedures.
11. For females: pregnancy or lactation.
12. For females of childbearing potential: not willing and able to use a contraceptive method, which the investigator considers reliable. Reliable methods for women are hormonal contraceptives, surgical intervention (e.g. tubal ligation), intrauterine device (IUD) and sexual abstinence. Women must use a reliable method from 6 weeks before the first administration of study medication until 3 weeks after the last administration of the study medication.
13. Participation in another clinical study involving a new chemical entity within 3 months and for studies involving biologicals 6 months prior to enrolment in this study.
14. The subject has received vaccination(s) within 1 month prior to enrollment, or is unwilling to postpone vaccinations for the duration of the study.
15. Subjects who are unable to comply with the requirements of the study or who in the opinion of the investigator should not participate in the study.

E.5 End points

E.5.1

Primary end point(s)

Safety
1. aPTT and INR
2. Platelet count (thrombocytes)
3. Clinical laboratory parameters: sodium, potassium, calcium, glucose, urea, creatinine, total bilirubin, AST(SGOT), ALT (SGPT), alkaline phosphatase (ALP), gamma glutamyl transpeptidase (GGT), creatinine kinase (CK), total protein, Troponin I and C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)
4. Hematology parameters: hemoglobin, red blood cell count (erythrocytes), hematocrit, total white blood cell count (leucocytes)
5. Adverse events and concomitant medication documented
6. Vital signs (pulse rate, blood pressure, body temperature) documented
7. General medical examination
8. ECG

E.5.1.1

Timepoint(s) of evaluation of this end point

Ad 1.: at screening, and pre-dose (immediately before start of ERT iv infusion) and 2 hours after subcutaneous injection and at Day 2 and 1 week (Week 25) and 3 weeks (Week 27) after the last dose of PPS.
Ad 2.: at screening, pre-dose at every visit and at Day 2 and 1 week and 3 weeks after the last dose of PPS.
Ad 3.: at screening, baseline, Week 12 and Week 25.
Ad 4.: at screening, Week 12 and Week 25.
Ad 5.: at every visit.
Ad 6.: at every visit.
Ad 7.: at screening and at Week 25.
Ad 8.: at screening and at Week 25.

E.5.2

Secondary end point(s)

1. Change from baseline in cytokines TNF-alpha, IL-1 and glycosaminoglycan (GAG)
2. Change from baseline in 6 minute walk test
3. Change from baseline in pulmonary function tests measured in the morning
4. Change from baseline in Grip Test
5. Change from baseline in CRP (C-reactive protein) and ESR (erythrocyte sedimentation rate)
6. Change from baseline in SF 36 Quality of Life
7. Change from baseline in pain assessment measured using Brief Pain Inventory
8. Change from baseline in range of motion measured by gait analysis
9. Pentosan polysulfate plasma concentrations measured pre-dose and 2 hours post-dose

E.5.2.1

Timepoint(s) of evaluation of this end point

Ad. 1. - 8.: at Week 12 and at Week 25.
Ad 9.: at Day 1, Week 2, Week 6, Week 10, Week 14, Week 18, Week 24 and once at Day 2 and Week 27.

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

Yes

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

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)

Yes

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

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

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.4.2.2

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)

Subjects, who benefit from the study drug treatment, can continue with the treatment at the investigator’s discretion as long as the subject benefits from treatment. bene pharmaChem will provide Pentosan Polysulphate SP54® to subjects who wish to continue treatment at no cost to the subject.

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

2014-05-28

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-05-28

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2015-04-27

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IMP with orphan designation in the indication
Orphan Designation Number:
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