Clinical Trials Register

Summary
EudraCT Number:	2014-001156-28
Sponsor's Protocol Code Number:	NAIMES/32
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-09-25
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2014-001156-28

A.3

Full title of the trial

A randomized, double-blind, placebo controlled study to assess the safety and the efficacy of Neridronate ampoules 25 mg, after repeated intramuscular administrations, in patients with Complex Regional Pain Syndrome type I (CRPS-I)

Studio randomizzato, in doppio cieco, controllato verso placebo, volto a valutare la sicurezza e l’efficacia di Neridronato 25 mg fiale, dopo ripetute somministrazioni intramuscolari, in pazienti con sindrome da dolore regionale complesso di tipo I (CRPS-I)

A.3.1

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

A.3.2

Name or abbreviated title of the trial where available

A.4.1

Sponsor's protocol code number

NAIMES/32

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	Abiogen Pharma SpA
B.1.3.4	Country	Italy
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	Abiogen Pharma SpA
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Abiogen Pharma SpA
B.5.2	Functional name of contact point	Marina Accoto
B.5.3	Address:
B.5.3.1	Street Address	Via Meucci 36
B.5.3.2	Town/ city	Ospedaletto (Pisa)
B.5.3.3	Post code	56121
B.5.3.4	Country	Italy
B.5.4	Telephone number	+0390503154214
B.5.5	Fax number	+0390503154285
B.5.6	E-mail	marina.accoto@abiogen.it

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	NERIXIA Soluzione iniettabile 25 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	ABIOGEN PHARMA S.p.A., Via Meucci 36, Ospedaletto – PISA
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	NERIXIA Soluzione iniettabile 25 mg
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	Intramuscular 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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for injection
D.8.4	Route of administration of the placebo	Intramuscular use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Complex Regional Pain Syndrome type I (CRPS-I)

Algodistrofia

E.1.1.1

Medical condition in easily understood language

Complex Regional Pain Syndrome type I (CRPS-I)

Algodistrofia

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	17.0
E.1.2	Level	LLT
E.1.2	Classification code	10049451
E.1.2	Term	Algodystrophy
E.1.2	System Organ Class	100000004852

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 the study is to assess the efficacy of the investigational medicinal product (IMP) as a proportion of patients showing a 50% or more, reduction of pain intensity, as measured using a 100 mm visual analogic scale (VAS), from the baseline visit to the last visit of the double-blind phase.

L'obbiettivo principale dello studio è valutare l'efficacia del farmaco in studio (IMP) in termini di percentuale di pazienti con il 50% o più, di riduzione dell’intensità del dolore, rispetto al basale misurata attraverso una scala VAS da 100 mm basale fino all’ultima visita della fase in doppio cieco.

E.2.2

Secondary objectives of the trial

To assess the improvement in pain intensity over the study period through VAS scale;
To assess the improvement in clinical signs and symptoms;
To assess the quality of life through generic and specific QoL questionnaires;
To assess the rescue analgesic consumption;
To assess the safety and local tolerability of Neridronate 25 mg administered by repeated i.m. injections;
To assess the effect of treatment on body mass index (BMI);
To assess the effect of treatment on the following markers of bone metabolism: serum Type I collagen cross-linked C-telopeptide (CTx); sclerostin, osteocalcin, N-terminal propeptide of type I procollagen (P1NP), recombinant human Dickkopf Homolog 1 (DKK1), parathyroid hormone (PTH) and vitamin D.

Valutare la riduzione dell’intensità del dolore percepito attraverso una scala VAS;
Valutare il miglioramento dei segni e dei sintomi clinici
Valutare la qualità della vita attraverso questionari specifici e generici
Valutare l’utilizzo di analgesici di supporto
Valutare la sicurezza e la tollerabilità locale di Neridronato 25 mg dopo ripetute somministrazioni intramuscolari;
Valutare l’effetto del trattamento sul BMI (Body Mass Index)
Valutare l’effetto del trattamento sui seguenti marcatori del metabolismo osseo: CTX (Telopeptide C-Terminale del Collagene di Tipo 1); sclerostina, osteocalcina, Propeptide N- terminale del procollagene di tipo I (P1NP), Ricombinante dickkopf homolog 1 umano, ormone paratiroideo (PTH) e Vitamina D.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Male or female outpatients aged 18 years or greater;
Patients with confirmed diagnosis of CRPS-I according to the International Association for the Study of Pain (IASP) criteria, i.e. the validated Budapest 2007 criteria (Harden et al, 2007, Appendix I) for research purposes and as evidenced by bone scintigraphy performed within 4 months before study entry;
Disease duration ≤ 4 months;
Patients with spontaneous pain (100 mm VAS scale) > 50 mm in the selected extremity (hand, foot, ankle);
Opioid analgesics, non-opioid analgesics, NSAIDs, anticonvulsants, antidepressant drugs and other non-drug therapies may be continued during the the double-blind phase provided the dose is stable for at least 4 weeks before treatment start;
Women of childbearing potential must have a negative pregnancy test (serum) before entering the study;
Women of childbearing potential must agree not to become pregnant and to breastfeed throughout the study period;
Patients with a co-operative attitude and able to adhere to study treatment and study protocol procedures and timelines;
Signature of written Inform Consent Form before any screening procedures.

Pazienti ambulatoriali di entrambi i sessi con età maggiore o uguale a 18 anni;
Pazienti con diagnosi confermata di CRPS-I in accordo ai criteri IASP (Intrenational Association per Study of Pain) di Budapest 2007 (Harden et al, 2007, Appendix I) validati per gli scopi di ricerca e confermata da scintigrafia ossea effettuata entro 4 mesi dall’entrata in studio;
Durata della patologia ≤ 4 mesi;
Pazienti con dolore spontaneo (su scala VAS da 100 mm) > di 50 nell’arto selezionato (mano, piede e caviglia);
Analgesici oppioidi e non oppioidi, FANS, anticonvulsivanti, antidepressivi e altre terapie non farmacologiche potranno essere continuate purché la dose sia stabile da almeno 4 settimane prima dell’inizio del trattamento;
Le donne in età fertile dovranno avere un test di gravidanza negativo (eseguito su siero) prima di entrare in studio;
Le donne in età fertile dovranno impegnarsi a non intraprendere una gravidanza e allattare al seno per tutta la durata dello studio;
Pazienti cooperativi e disponibili ad aderire al trattamento in studio, alle procedure e alle tempistiche di protocollo;
Firma del Consenso Informato scritto prima di qualsiasi procedura di screening.

E.4

Principal exclusion criteria

Documented peripheral neuropathy, including diabetic neuropathy and other metabolic or toxic neuropathies;
Bilirubin, ALT, AST, alkaline phosphatase levels > 2 ULN at the screening visit (Visit 0);
Current signs or symptoms of severe and/or progressive or uncontrolled hepatic, renal, endocrine, haematological, cardiac pulmonary, neurological disease based on investigator judgement;
Any other serious medical condition or laboratory abnormality or psychiatric illness preventing the patient from signing the Informed Consent Form;
Recent tooth extraction (in the past 3 months prior to Visit 1), unhealed or infected extraction site, significant dental/periodontal disease that may pre-dispose to need for tooth extraction or other invasive dental procedures during the trial;
Evidence of denture-related gum trauma or injury;
Prior development of an allergic reaction/hypersensitivity while administered bisphosphonates;
Prior treatment with bisphosphonates in the previous 12 months;
Allergy, sensitivity or intolerance to study drug and/or study drug formulation ingredients;
Patients unable to give a valid informed consent;
Patients unlikely to comply with the protocol or unable to understand the nature, scope and possible consequences of the study;
Patients who received any investigational new drug within the last 12 weeks;
Patients who have been previously enrolled in this study;
Employees of the investigator or study centre (i.e., principal investigator, sub-investigator, study coordinators, other study staff, employees, or contractors of each), with direct involvement in the proposed study or other studies under the direction of that investigator and/or study centre, as well as family members of the employees or the investigator.

Neuropatie periferiche documentate, compresa la neuropatia diabetica e altre neuropatie metaboliche o tossiche;
Bilirubina, ALT, AST, fosfatasi alcalina a livelli > 2 il limite superiore di normalità alla visita di screening (Visita 0);
Segni e sintomi concomitanti di patologie epatiche, renali, endocrine, ematologiche, cardio polmonari, neurologiche gravi e/o in progressione o non controllate a giudizio dello sperimentatore;
Qualsiasi altra condizione medica grave o anomalia di laboratorio o disturbo psichico che possa impedire al paziente di firmare il consenso informato;
Recente estrazione dentaria (nei 3 mesi prima di Visita 1), sito di estrazione non cicatrizzato o infetto, significative malattie dentali/periodontali che possono richiedere un estrazione dentaria o alter procedure dentali invasive durante lo studio;
Evidenza di lesioni o traumi gengivali;
Reazioni allergiche/ipersensibilità sviluppate in precedenza durante la somministrazione di bifosfonati;
Trattamento con bifosfonati nei 12 mesi precedenti;
Allergia, sensibilità o intolleranza al farmaco in studio o ad uno dei degli eccipienti;
Paziente incapace di dare una valido consenso informato;
Pazienti incapaci di rispettare il protocollo o di comprenderne la natura, lo scopo e le possibili conseguenze dello studio;
Pazienti che hanno assunto qualsiasi farmaco sperimentale durante le ultime 12 settimane;
Pazienti che sono stati precedentemente arruolati in questo studio;
Collaboratori dello sperimentatore o del centro di sperimentazione (es. sperimentatore principale, co-sperimentatore, coordinatori di studio, altri componenti dello staff, dipendenti o con altri contratti), con diretto coinvolgimento nello studio proposto o in altri studi sotto la direzione di quello sperimentatore e/o centro, così come familiari dei dipendenti o dello sperimentatore.

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint will be the proportion of patients showing a reduction ≥ 50% of pain intensity graded on a 100 mm VAS scale from baseline to Day 30 (Visit 4).

Percentuale di pazienti che mostrano una riduzione dell’intensità del dolore ≥ 50% - misurato attraverso una scala VAS 100 mm dalla visita Basale al giorno 30 (Visita 4).

E.5.1.1

Timepoint(s) of evaluation of this end point

See item E.5.1

Vedere item E.5.1

E.5.2

Secondary end point(s)

The secondary efficacy variables are:
Pain graded on a 100 mm VAS scale recorded at the intermediate visits;
Clinical signs and symptoms based on a 0-3 rating scale (none, mild, moderate, severe): swelling and pain on passive motion at the intermediate visits; Clinical symptoms based on a dichotomous (present/absent) evaluation: sweating, allodynia and hyperalgesia at the intermediate visits; Mc Gill Pain Questionnaire Short-Form (SF); At visit 0, 1, 4, 5, 6 e 7
Quality of life: SF-36 questionnaire; At visit 0, 1, 4, 5, 6 e 7
Rescue medication consumption: number of tablets of Paracetamol 500 mg administered, reported on a patient daily diary at visit 2, 3, 4;
Markers of bone metabolism: serum CTx, sclerostin, osteocalcin, P1NP, DKK1, PTH and vitamin D. At visit 1, 4, 4a (if Applicable), 5, 6, 7

The safety variables of the study are:
Adverse Events (AEs) occurring At any time during the study;
Hematology and blood chemistry At visit 0, 1, 3, 4, 4a,4d (if Applicable), 5, 6, 7;
Physical examination, including measurement of vital signs: weight, height (for BMI assessment), blood pressure and heart rate At visit 0,1, 4, 4a (if Applicable),5, 6, 7;
Injection site pain (VAS) At visit 1,2,3;
Injection site reddening score: At visit 1,2,3
Injection site hardening score: At visit 1,2,3

Efficacia:
Dolore misurato attraverso una scala VAS da 100 mm, rilevato a tutte le visite intermedie ;
Segni e sintomi clinici quali gonfiore e dolore al movimento passivo valutati con un punteggio (0-3; assente, lieve, moderata, grave) rilevato a tutte le visite intermedie; Sudorazione, allodinia e iperalgesia valutate come assente/presente rilevato a tutte le visite intermedie;
Questionari Mc Gill Pain e SF-36 rilevato a visita 0, 1, 4, 5, 6 e 7;
Consumo di terapia di supporto: numero di compresse di Paracetamolo 500 mg assunte sulla base del diario giornaliero compilato dal paziente rilevato a visita 2, 3, 4;
Marker del metabolismo osseo: serum CTx, sclerostina, osteocalcina, P1NP, DKK1, PTH and vitamina D. rilevato a visita 1, 4, 4a(se applicabile), 5, 6, 7;

Sicurezza:
Eventi avversi (AEs) intercorsi in qualsiasi momento durante lo studio;
Ematologia e biochimica rilevato a visita 0, 1, 3, 4, 4a,4d (se applicabile), 5, 6, 7;
Esame fisico, inclusa la rilevazione dei segni vitali (BMI, pressione sanguigna, frequenza cardiaca); rilevato a visita 0,1, 4, 4a (se applicabile),5, 6, 7;
Dolore nel sito di iniezione (VAS) rilevato a visita 1,2,3;
Punteggio relativo al rossore nel sito di iniezione rilevato a visita 1,2,3;
Punteggio relativo all’indurimento nel sito di iniezione; rilevato a visita 1,2,3;

E.5.2.1

Timepoint(s) of evaluation of this end point

See item E.5.2

Vedere item E.5.2

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)

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

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)

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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.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)

At the end of the study the investigator will decide the most appropriate therapy for the rest of the patient.

Al termine dello studio lo sperimentatore deciderà la terapia più appropriata per il proseguo del paziente.

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

2014-11-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-10-28

P. End of Trial
P.	End of Trial Status	Completed

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