Clinical Trials Register

Summary
EudraCT Number:	2014-001453-17
Sponsor's Protocol Code Number:	PVO-1A-201
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:	2015-02-25
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

UK - MHRA

A.2

EudraCT number

2014-001453-17

A.3

Full title of the trial

A Phase 2 Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study of a RARγ-Specific Agonist (Palovarotene) in the Treatment of Preosseous Flare-ups in Subjects with Fibrodysplasia Ossificans Progressiva (FOP).

A.3.1

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

The Study of an Investigational Drug, Palovarotene, in the Treatment of Preosseous Flare-ups in Subjects with Fibrodysplasia Ossificans Progressiva.

A.4.1

Sponsor's protocol code number

PVO-1A-201

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02190747

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/127/2015

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Clementia Pharmaceuticals 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	Clementia Pharmaceuticals 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	Medpace France
B.5.2	Functional name of contact point	Clinical Trials Information
B.5.3	Address:
B.5.3.1	Street Address	Le Rhône Alpes 235, cours Lafayette
B.5.3.2	Town/ city	Lyon
B.5.3.3	Post code	69006
B.5.3.4	Country	France
B.5.4	Telephone number	33437 53 09 80
B.5.5	Fax number	33972 36 97 87
B.5.6	E-mail	regsubmissions@medpace.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/3/14/1368
D.3 Description of the IMP
D.3.1	Product name	Palovarotene
D.3.2	Product code	Palovarotene
D.3.4	Pharmaceutical form	Capsule, hard
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	PALOVAROTENE
D.3.9.1	CAS number	410528-02-8
D.3.9.3	Other descriptive name	PALOVAROTENE
D.3.9.4	EV Substance Code	SUB75998
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	1.5 to 10
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/3/14/1368
D.3 Description of the IMP
D.3.1	Product name	Palovarotene
D.3.2	Product code	Palovarotene
D.3.4	Pharmaceutical form	Oral powder in sachet
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	PALOVAROTENE
D.3.9.1	CAS number	410528-02-8
D.3.9.3	Other descriptive name	PALOVAROTENE
D.3.9.4	EV Substance Code	SUB75998
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	1.5 to 10
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule, hard
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Oral powder in sachet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Fibrodysplasia Ossificans Progressiva (FOP) is a rare, severely disabling disease characterized by painful, recurrent episodes of soft tissue swelling (flare-ups) and abnormal heterotopic ossification (HO) in muscles, tendons, and ligaments. Lesions begin in early childhood and lead to progressive ankyloses of major joints with resultant loss of movement. Prognosis is poor and median life expectancy is 40 years.

E.1.1.1

Medical condition in easily understood language

FOP is a rare, severely disabling disease characterized by painful, recurrent episodes of soft tissue swelling (flare-ups) and abnormal heterotopic ossification in muscles, tendons, and ligaments.

E.1.1.2

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.0
E.1.2	Level	PT
E.1.2	Classification code	10068715
E.1.2	Term	Fibrodysplasia ossificans progressiva
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

To evaluate the ability of different doses of palovarotene to prevent heterotopic ossification at the flare-up site in subjects with FOP as assessed by plain radiographs.

E.2.2

Secondary objectives of the trial

•To investigate the safety of palovarotene (IP) vs placebo in FOP subjects w/flare-ups (FUps) •To evaluate (eval) effect of IP on ROM as assessed by goniometer and global assessment of movement •To eval effect of IP on physical function using age-appropriate FOP-PFQs •To eval effect of IP on physical/mental health using age-appropriate PROMIS Global Health Scales •To eval effects of IP on pain/swelling associated with FUps using NRS or FPS-R in subjects under 8 years of
age •To eval use of assistive devices/adaptations for daily living by FOP subjects •To eval effects of IP on bone formation at the FUp site as assessed by low dose CT •To eval effects of IP on soft tissue
swelling/cartilage formation at FUp site as assessed by MRI; or soft tissue swelling as assessed by ultrasound •To eval cartilage, bone, angiogenesis, inflammation biomarkers & explore correlations b/w changes from baseline in biomarkers & clinical efficacy •To eval PK of IP at steady-state in FOP subjects

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

•Male or female at least 6 years of age.
•Subjects clinically diagnosed with classic FOP.
•Symptomatic onset of a distinct flare-up within 7 days of Study Day 1 (start of study drug) and defined by the presence of at least two of six of the following symptoms: pain, soft tissue swelling, decreased ROM, stiffness, redness, and warmth. Symptoms must be reported by the subject during the pre-screening period, be consistent with their previous flare-ups, include a subject-reported onset date, and flare-up confirmed by the Investigator at the Screening visit.
•Flare-up is at an appendicular area (upper or lower extremity), abdomen, or chest; and subject has received, is receiving, or is willing to receive treatment per standard of care, which may or may not include prednisone (2 mg/kg PO [per os] to a maximum dose of 100 mg daily) for 4 days.

E.4

Principal exclusion criteria

•Weight <20 kg.
•Intercurrent non-healed fracture at any location.
•Complete immobilization of joint at site of flare-up.
•The inability of the subject to undergo imaging assessments using plain radiographs.
•If currently using vitamin A or beta carotene, multivitamins containing vitamin A or beta carotene, herbal preparations, fish oil, and unable or unwilling to discontinue use of these products for the duration of the study.
•Exposure to synthetic oral retinoids in the past 30 days prior to Screening (signature of the informed consent).
•Concurrent treatment with tetracycline due to the potential increased risk of pseudotumor cerebri.
•History of allergy or hypersensitivity to retinoids or lactose.
•Concomitant medications that are inhibitors or inducers of CYP450 3A4 activity.

E.5 End points

E.5.1

Primary end point(s)

The percentage of subject responders as defined by no or minimal new HO at the flare-up site compared with baseline as assessed by plain radiographs at Study Day 42.

E.5.1.1

Timepoint(s) of evaluation of this end point

The percentage of subject responders as defined by no or minimal new HO at the flare-up site compared with baseline as assessed by plain radiographs at Study Day 42.

E.5.2

Secondary end point(s)

1. Proportion of subjects across the seven HO scores (0-6) at the flare-up site as assessed by plain radiographs at Study Days 42 and 84.
2. Change from baseline in amount (area) of new heterotopic bone formed at the flare-up site assessed by plain radiographs at Study Days 42 and 84.
3. Percentage of subject responders as defined by no or minimal new HO at the flare-up site as compared with baseline as assessed by plain radiographs at Study Day 84.
4. Change from baseline in cartilage, bone, angiogenesis, and inflammation biomarkers at Study Days 14, 28, 42, and 84.
5. Change from baseline in amount of bone formation (volume) at Study Days 42 and 84 as assessed by low dose CT scan.
6. Presence of soft tissue swelling and/or cartilage by MRI at Study Days 42 and 84; or presence of soft tissue swelling by ultrasound (US) at Study Days 42 and 84 in subjects unable to undergo MRI.
7. Change from baseline in active ROM measured by goniometer of the relevant joint at Study Days 42 and 84.
8. Subject and Investigator global assessment of movement at Study Days 42 and 84.
9. Change from baseline in pain and swelling at the flare-up site using NRS, or the FPS-R for subjects under 8 years of age, for each symptom at Study Days 14, 28, 42, 63, and 84.
10. Change from baseline in the use of assistive devices and adaptations for daily living by FOP subjects at Study Days 42 and 84.
11. Duration of active, symptomatic flare-up (start date and end date), as assessed by the subject and the Investigator.
12. Change from baseline in physical function using age-appropriate forms of the FOP-PFQ at Study Days 14, 28, 42, 63, and 84.
13. Change from baseline in physical and mental health using age-appropriate forms of the PROMIS Global Health Scales at Study Days 14, 28, 42, 63, and 84.
14. Assessment of PK parameters at steady-state on Study Day 14, and on Study Day 28 or 42.

E.5.2.1

Timepoint(s) of evaluation of this end point

The various secondary endpoints will be measured at some or all of the following study days: 14, 28, 42, 63, and 84.

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

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

Duration of Treatment; Use of Assistive Devices

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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

Yes

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

Argentina

United States

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

Number of subjects for this age range:

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)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

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)

Consistent with pre-study treatment, if any. In addition, subjects completing the study will be given the opportunity to enroll into an open label extension study (Study PVO-1A-202; to be submitted as a separate CTA) provided they meet eligibility requirements.

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

2015-04-22

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-07-07

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2016-05-23

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