Clinical Trials Register

Summary
EudraCT Number:	2020-003602-31
Sponsor's Protocol Code Number:	TRM-201-HA-301
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2021-07-27
Trial 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

Italy - Italian Medicines Agency

A.2

EudraCT number

2020-003602-31

A.3

Full title of the trial

A Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Phase III Study with a Long-Term, Open-label Extension to Evaluate the Efficacy and Safety of TRM-201 (Rofecoxib) in Patients with Hemophilic Arthropathy

Studio di fase III randomizzato, in doppio cieco, controllato con placebo, a gruppi paralleli, con estensione in aperto, a lungo termine, per valutare l’efficacia e la sicurezza di TRM-201 (rofecoxib) in pazienti affetti da artropatia emofilica

A.3.1

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

Rofecoxib Efficacy and Safety Evaluation Trial in Hemophilic Arthropathy

Studio di valutazione dell'efficacia e della sicurezza del rofecoxib nell'artropatia emofila

A.3.2

Name or abbreviated title of the trial where available

A.4.1

Sponsor's protocol code number

TRM-201-HA-301

A.5.4

Other Identifiers

Name:

IND

Number:

132926

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	Tremeau 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	Tremeau 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	Tremeau Pharmaceuticals, Inc.
B.5.2	Functional name of contact point	Clinical Operations
B.5.3	Address:
B.5.3.1	Street Address	53 Main St. Suite 202
B.5.3.2	Town/ city	Concord, MA
B.5.3.3	Post code	01742
B.5.3.4	Country	United States
B.5.4	Telephone number	6174850250
B.5.5	Fax number	6174850991
B.5.6	E-mail	ClinicalOperations@tremeaurx.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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Rofecoxib
D.3.2	Product code	[TRM-201]
D.3.4	Pharmaceutical form	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.3.9.1	CAS number	162011-90-7
D.3.9.2	Current sponsor code	RM-201
D.3.9.4	EV Substance Code	SUB04261MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	17500
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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.2.1.1.1	Trade name	Acetaminophen and codeine phosphate
D.2.1.1.2	Name of the Marketing Authorisation holder	Mallinckrodt
D.2.1.2	Country which granted the Marketing Authorisation	United States
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	Acetaminophen and codeine phosphate
D.3.2	Product code	[.]
D.3.4	Pharmaceutical form	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.3.9.2	Current sponsor code	.
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	120
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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	controlled substance

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	Tablet
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

Hemophilic Arthropathy

artropatia emofilica

E.1.1.1

Medical condition in easily understood language

Hemophilic Arthropathy

artropatia emofilica

E.1.1.2

Therapeutic area

Diseases [C] - Blood and lymphatic diseases [C15]

MedDRA Classification

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 efficacy of TRM-201 (rofecoxib) 17.5 mg versus placebo in patients with hemophilic arthropathy as measured by patient assessment of hemophilic arthropathy average pain intensity.

Valutare l’efficacia di TRM-201 (rofecoxib) 17,5 mg rispetto al placebo in pazienti con artropatia emofilica misurata mediante la valutazione dell’intensità media del dolore nell’artropatia emofilica da parte del paziente.

E.2.2

Secondary objectives of the trial

1. To evaluate the efficacy of TRM-201 (rofecoxib) 17.5 mg versus placebo on physical function in patients with hemophilic arthropathy as measured by the Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function-Short Form 10a.
2. To evaluate the efficacy of TRM-201 (rofecoxib) 17.5 mg versus placebo in patients with hemophilic arthropathy as measured by patient assessment of hemophilic arthropathy worst pain intensity.
3. To evaluate the efficacy of TRM-201 (rofecoxib) 17.5 mg versus placebo in patients with hemophilic arthropathy as measured by the Pain Interference Domain from the Brief Pain Inventory (BPI).
4. To evaluate the efficacy of TRM-201 (rofecoxib) 17.5 mg versus placebo in patients with hemophilic arthropathy as measured by patient assessment of average hemophilic arthropathy pain intensity in the selected most painful joint.

1. Valutare l’efficacia di TRM-201 (rofecoxib) 17,5 mg rispetto al placebo sulla funzione fisica in pazienti con artropatia emofilica misurata mediante il Modulo breve 10a sulla funzione fisica del Sistema informativo di misurazione degli esiti riferiti dal paziente (PROMIS).
2. Valutare l’efficacia di TRM-201 (rofecoxib) 17,5 mg rispetto al placebo in pazienti con artropatia emofilica misurata mediante la valutazione dell’intensità maggiore del dolore nell’artropatia emofilica da parte del paziente.
3. Valutare l’efficacia di TRM-201 (rofecoxib) 17,5 mg rispetto al placebo in pazienti con artropatia emofilica misurata mediante il Dominio di interferenza del dolore del Breve inventario del dolore (BPI).
4. Valutare l’efficacia di TRM-201 (rofecoxib) 17,5 mg rispetto al placebo in pazienti con artropatia emofilica misurata mediante la valutazione da parte del paziente dell’intensità media del dolore nell’artropatia emofilica nell’articolazione selezionata più dolorosa.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Diagnosis of hemophilia A or B
• Either on a stable prophylaxis regimen for their bleeding disorder (factor,
bypassing agent, or nonfactor product therapy) OR currently taking or
agree to initiate a gastroprotective agent (esomeprazole) for the duration of
the trial
• Diagnosis of Hemophilic Arthopathy for at least 6 months prior to screening
• Chronic symptomatic pain in one or more joint(s) on 20 of the 30 days prior
to screening.
• Able and willing to wash out of non-study analgesic medications/agents
for at least 5 days prior to Randomization including: acetaminophen
(paracetamol), NSAIDs, opioids, cannabinoids, topical analgesics,
benzodiazepines, gabapentin/pregabalin-containing products and other
antiepileptic drugs used for pain
• Primary source of pain is due to Hemophilic Arthropathy

Diagnosi di emofilia A o B
- In regime di profilassi stabile per il disturbo emorragico (terapia farmacologica con fattore, agente bypassante o prodotto senza fattore) OPPURE attuale assunzione o consenso ad avviare un agente gastroprotettivo (esomeprazolo) per la durata della sperimentazione. Tutti i pazienti con inibitori che non sono sottoposti a una terapia farmacologica stabile con un prodotto senza fattore (per es., emicizumab) devono assumere o accettare di avviare un agente gastroprotettivo (esomeprazolo) per la durata della sperimentazione.
- Diagnosi di HA da almeno 6 mesi prima dello screening
-Dolore sintomatico cronico in una o più articolazioni nei 20 dei 30 giorni precedenti lo screening.
- Capacità e volontà di eseguire il wash-out dei farmaci/degli agenti analgesici non appartenenti allo studio per almeno 5 giorni prima della randomizzazione tra cui: acetaminofene (paracetamolo), NSAIDs, oppioidi, prodotti contenenti cannabinoidi, analgesici topici benzodiazepine, prodotti contenenti gabapentin/pregabalin e altri farmaci antiepilettici utilizzati per il dolore.
- La fonte primaria del dolore è l'artropatia emofilica

E.4

Principal exclusion criteria

• Taking opioids for greater than 4 days per week prior to screening
• Has a history of advanced renal disease or severe liver disease (within the
last 6 months)
• Receiving emicizumab while also receiving activated prothrombin complex
concentrate (FEIBA)
• Uncontrolled or poorly controlled hypertension
• History of major cardiac or cerebrovascular disease
• History of an upper GI perforation, obstruction, or major GI bleed or current
evidence of GI bleeding
• Has active hepatitis C or hepatitis B infection or uncontrolled HIV. Note:
Patients who are HIV positive are allowed to participate if considered to be
controlled.
• Has a positive drug screen for all prohibited drugs of potential abuse at
screening
• Has had an intra-articular injection (within 3 months), initiated physical
therapy (within 30 days) or has had orthopedic surgery (within 4 months) prior to screening

- Assunzione di oppiodi per più di 4 giorni alla settimana prima dello screening
- Avere un’anamnesi di malattia renale avanzata (entro gli ultimi 6 mesi)
- Pazienti che ricevono emicizumab che stanno anche ricevendo il complesso protrombinico concentrato attivato (FEIBA).
- ipertensione non controllata o scarsamente controllata
- gravi sintomi ischemici cardiaci o cerebrovascolari
- anamnesi di perforazione del tratto GI superiore, ostruzione o sanguinamento gastrointestinale maggiore o evidenza clinica attuale di sanguinamento GI
- Presentare epatite C attiva o infezione attiva da epatite B o HIV non controllato. Nota: I pazienti positivi all’HIV possono partecipare se considerati controllati
- Allo screening, avere un risultato positivo all’esame tossicologico per le sostanze di potenziale abuso
- Ha subito un'iniezione intra-articolare (entro 3 mesi), ha iniziato una terapia fisica (entro 30 giorni) o ha subito un intervento chirurgico ortopedico (entro 4 mesi) prima dello screening

E.5 End points

E.5.1

Primary end point(s)

The change from baseline in the patient assessment of the daily hemophilic arthropathy pain score (average pain over the past 24 hours on a 0- to 10-point numeric rating scale) at Week 12 (assessed daily).

Variazione rispetto al basale nella valutazione da parte del paziente del punteggio relativo al dolore giornaliero dell’artropatia emofilica (dolore medio nelle ultime 24 ore su una scala di valutazione numerica da 0 a 10 punti) alla Settimana 12 (valutato ogni giorno)

E.5.1.1

Timepoint(s) of evaluation of this end point

As per the Protocol

come da protocollo

E.5.2

Secondary end point(s)

1. The change from baseline in the PROMIS Physical Function-Short Form 10a score at Week 12 (assessed once weekly).
2. The change from baseline in the patient assessment of the daily hemophilic arthropathy pain score (worst pain over the past 24 hours on a 0- to 10-point numeric rating scale) at Week 12 (assessed daily).
3. The change from baseline in the Pain Interference score from the BPI at Week 12 (assessed once weekly).
4. The change from baseline in the patient assessment of hemophilic arthropathy pain intensity in the selected most painful joint (average pain over the past 24 hours) at Week 12 (assessed once weekly). Note: The same joint is to be followed throughout Part I.

Other Secondary Endpoints
1. The change from baseline in the PROMIS Sleep Disturbance-Short Form 4a score at Week 12 (assessed at clinic visits).
2. The change from baseline in the PGI-S – Joint Symptoms (assessed at baseline and end of Part I).
3. The change from baseline in the EQ-5D-5L Health Status score at Week 12 (assessed at clinic visits).

1. Variazione rispetto al basale nel punteggio del Modulo breve 10a sulla funzione fisica del PROMIS alla Settimana 12 (valutato una volta a settimana).
2. Variazione rispetto al basale nella valutazione da parte del paziente del punteggio relativo al dolore giornaliero dell’artropatia emofilica (dolore peggiore nelle ultime 24 ore su una scala di valutazione numerica da 0 a 10 punti) alla Settimana 12 (valutato ogni giorno).
3. Variazione rispetto al basale nel punteggio di interferenza del dolore del BPI alla Settimana 12 (valutato una volta alla settimana).
4. Variazione rispetto al basale nella valutazione da parte del paziente dell’intensità del dolore nell’artropatia emofilica nell’articolazione selezionata più dolorosa (dolore medio nelle ultime 24 ore) alla Settimana 12 (valutata una volta a settimana). Nota: la stessa articolazione deve essere seguita durante tutta la Parte I.
Altri endpoint secondari:
1. Variazione rispetto al basale nel punteggio del Modulo breve 4a sul disturbo del sonno del PROMIS alla Settimana 12 (valutato in occasione delle visite cliniche).
2. Variazione rispetto al basale nel PGI-S - Sintomi articolari (valutati al basale e alla fine della Parte I).
3. Variazione rispetto al basale nel punteggio del questionario EQ-5D-5L

E.5.2.1

Timepoint(s) of evaluation of this end point

As per the Protocol

come da protocollo

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

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

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

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)

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

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

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

Information not present in EudraCT

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

Brazil

Canada

Russian Federation

Turkey

Ukraine

United States

Italy

Poland

Spain

United Kingdom

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.1.1.1

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)

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:

130

F.1.3

Elderly (>=65 years)

Yes

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

Yes

F.3.3.7.1

Details of other specific vulnerable populations

Trial involves Minors

Lo studio prevede il coinvolgimento di minori

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

160

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 study intervention is foreseen following the end of study.

Nessun intervento è previsto dopo la fine dello studio.

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

2021-10-29

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-12-15

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2022-09-09

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