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Clinical Trial Results:
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)

Summary
EudraCT number	2014-001156-28
Trial protocol	IT
Global end of trial date	18 Mar 2020

Results information
Results version number	v1(current)
This version publication date	13 Dec 2021
First version publication date	13 Dec 2021
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

NAIMES/32

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Abiogen Pharma S.p.A.

Sponsor organisation address

Via Meucci, 36, Pisa, Italy,

Public contact

Fabrizio Nannipieri, Abiogen Pharma S.p.A., fabrizio.nannipieri@abiogen.it

Scientific contact

Fabrizio Nannipieri, Abiogen Pharma S.p.A., fabrizio.nannipieri@abiogen.it

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

19 May 2021

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

18 Mar 2020

Was the trial ended prematurely?

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 analogue scale (VAS), from the baseline visit to the last visit of the double-blind phase.

Protection of trial subjects

In case of insufficient pain relief during the double-blind phase, patients are allowed to take Paracetamol 500 mg oral tablet as rescue medication, up to a maximum daily dose of 2 g.

Background therapy

Evidence for comparator

Actual start date of recruitment

13 Apr 2015

Long term follow-up planned

Yes

Long term follow-up rationale

Efficacy, Safety

Long term follow-up duration

10 Months

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Italy: 78

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

M, F. Age ≥ 18 years Confirmed diagnosis of CRPS-I Disease duration ≤ 4 months Spontaneous pain (100 mm VAS scale) > 50 mm in the selected extremity Opioid and non-opioid analgesics, NSAIDs, anticonvulsants, antidepressant drugs and other non-drug therapies may be continued provided the dose is stable for at least 4 weeks before treatment start

Period 1 title

Double blind phase

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Are arms mutually exclusive

Yes

Neridronate 25 mg i.m.

Arm description

Arm type

Experimental

Investigational medicinal product name

Neridronate 25 mg i.m.

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

One i.m. injection for 16 consecutive days.

Placebo i.m.

Arm description

Arm type

Placebo

Investigational medicinal product name

Placebo i.m.

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

One i.m. injection for 16 consecutive days.

Number of subjects in period 1	Neridronate 25 mg i.m.	Placebo i.m.
Started	41	37
Completed	40	34
Not completed	1	3
Consent withdrawn by subject	1	1
Lost during double-blind	-	1
Failure to comply with protocol	-	1

Period 2 title

Open label phase

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Neridronate 100 mg i.v.

Arm description

Arm type

Approved therapy

Investigational medicinal product name

Neridronate 100 mg i.v.

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

A dose of four 100 mg i.v. infusions (one every third day) in a 10-day treatment cycle (i.e. on Days 1, 4, 7 and 10 of the cycle).

No treatment

Arm description

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 2	Neridronate 100 mg i.v.	No treatment
Started	32	42
Completed	31	42
Not completed	1	0
Consent withdrawn by subject	1	-

Period 3 title

Follow-up phase

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Neridronate 25 mg i.m.

Arm description

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Neridronate 100 mg i.v.

Arm description

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Placebo i.m.

Arm description

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 3	Neridronate 25 mg i.m.	Neridronate 100 mg i.v.	Placebo i.m.
Started	40	31	2
Completed	35	23	2
Not completed	5	8	0
Consent withdrawn by subject	2	5	-
Lost to follow-up	3	3	-

Baseline characteristics

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Reporting group title

Neridronate 25 mg i.m.

Reporting group description

Reporting group title

Placebo i.m.

Reporting group description

Reporting group values	Neridronate 25 mg i.m.	Placebo i.m.	Total
Number of subjects	41	37	78
Age categorical
Units: Subjects
Adults (18-64 years)	30	22	52
From 65-84 years	11	15	26
Age continuous
Units: years
arithmetic mean (standard deviation)	59.3 ( 10.23 )	59.7 ( 10.53 )	-
Gender categorical
Units: Subjects
Female	25	27	52
Male	16	10	26

End points

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Reporting group title

Neridronate 25 mg i.m.

Reporting group description

Reporting group title

Placebo i.m.

Reporting group description

Reporting group title

Neridronate 100 mg i.v.

Reporting group description

Reporting group title

No treatment

Reporting group description

Reporting group title

Neridronate 25 mg i.m.

Reporting group description

Reporting group title

Neridronate 100 mg i.v.

Reporting group description

Reporting group title

Placebo i.m.

Reporting group description

Primary: Proportion of Patients Showing a Reduction >= 50% in VAS for Pain at Day 30

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End point title

Proportion of Patients Showing a Reduction >= 50% in VAS for Pain at Day 30

End point description

End point type

Primary

End point timeframe

Day 30

End point values	Neridronate 25 mg i.m.	Placebo i.m.
Number of subjects analysed	41	37
Units: percent
number (confidence interval 95%)	65.9 (49.4 to 79.9)	29.7 (15.9 to 47.0)

Comparison between Neridronate and Placebo

Comparison groups

Placebo i.m. v Neridronate 25 mg i.m.

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0017

Method

Fisher exact

Confidence interval

Adverse events

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Timeframe for reporting adverse events

From the time of subject signing the ICF to the end of the study

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

22.0

Reporting group title

Neridronate 25 mg i.m. - double blind phase

Reporting group description

Reporting group title

Placebo i.m. - double blind phase

Reporting group description

Reporting group title

Neridronate 100 mg i.v. - open label phase

Reporting group description

Reporting group title

Neridronate 25 mg i.m. - follow-up phase

Reporting group description

Reporting group title

Placebo i.m. - follow-up phase

Reporting group description

Serious adverse events	Neridronate 25 mg i.m. - double blind phase	Placebo i.m. - double blind phase	Neridronate 100 mg i.v. - open label phase	Neridronate 25 mg i.m. - follow-up phase	Placebo i.m. - follow-up phase
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 41 (0.00%)	0 / 37 (0.00%)	0 / 32 (0.00%)	3 / 41 (7.32%)	0 / 35 (0.00%)
number of deaths (all causes)	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0
Injury, poisoning and procedural complications
Forearm fracture
subjects affected / exposed	0 / 41 (0.00%)	0 / 37 (0.00%)	0 / 32 (0.00%)	1 / 41 (2.44%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subarachnoid haemorrhage
subjects affected / exposed	0 / 41 (0.00%)	0 / 37 (0.00%)	0 / 32 (0.00%)	1 / 41 (2.44%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skull fracture
subjects affected / exposed	0 / 41 (0.00%)	0 / 37 (0.00%)	0 / 32 (0.00%)	1 / 41 (2.44%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rib fracture
subjects affected / exposed	0 / 41 (0.00%)	0 / 37 (0.00%)	0 / 32 (0.00%)	1 / 41 (2.44%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Hypertensive crisis
subjects affected / exposed	0 / 41 (0.00%)	0 / 37 (0.00%)	0 / 32 (0.00%)	1 / 41 (2.44%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Neridronate 25 mg i.m. - double blind phase	Placebo i.m. - double blind phase	Neridronate 100 mg i.v. - open label phase	Neridronate 25 mg i.m. - follow-up phase	Placebo i.m. - follow-up phase
Total subjects affected by non serious adverse events
subjects affected / exposed	27 / 41 (65.85%)	14 / 37 (37.84%)	12 / 32 (37.50%)	1 / 41 (2.44%)	1 / 35 (2.86%)
Nervous system disorders
Headache
subjects affected / exposed	7 / 41 (17.07%)	3 / 37 (8.11%)	1 / 32 (3.13%)	0 / 41 (0.00%)	0 / 35 (0.00%)
occurrences all number	8	3	2	0	0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	10 / 41 (24.39%)	1 / 37 (2.70%)	3 / 32 (9.38%)	0 / 41 (0.00%)	1 / 35 (2.86%)
occurrences all number	18	1	3	0	1
Injection site pain
subjects affected / exposed	7 / 41 (17.07%)	4 / 37 (10.81%)	0 / 32 (0.00%)	0 / 41 (0.00%)	0 / 35 (0.00%)
occurrences all number	8	7	0	0	0
Malaise
subjects affected / exposed	4 / 41 (9.76%)	0 / 37 (0.00%)	1 / 32 (3.13%)	0 / 41 (0.00%)	0 / 35 (0.00%)
occurrences all number	6	0	1	0	0
Pain
subjects affected / exposed	4 / 41 (9.76%)	3 / 37 (8.11%)	1 / 32 (3.13%)	0 / 41 (0.00%)	0 / 35 (0.00%)
occurrences all number	9	5	1	0	0
Asthenia
subjects affected / exposed	3 / 41 (7.32%)	2 / 37 (5.41%)	3 / 32 (9.38%)	0 / 41 (0.00%)	0 / 35 (0.00%)
occurrences all number	3	4	3	0	0
Acute phase reaction
subjects affected / exposed	1 / 41 (2.44%)	1 / 37 (2.70%)	2 / 32 (6.25%)	0 / 41 (0.00%)	0 / 35 (0.00%)
occurrences all number	1	1	3	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	7 / 41 (17.07%)	4 / 37 (10.81%)	2 / 32 (6.25%)	0 / 41 (0.00%)	0 / 35 (0.00%)
occurrences all number	10	5	2	0	0
Myalgia
subjects affected / exposed	7 / 41 (17.07%)	1 / 37 (2.70%)	2 / 32 (6.25%)	0 / 41 (0.00%)	0 / 35 (0.00%)
occurrences all number	14	1	2	0	0
Pain in extremity
subjects affected / exposed	6 / 41 (14.63%)	1 / 37 (2.70%)	2 / 32 (6.25%)	0 / 41 (0.00%)	0 / 35 (0.00%)
occurrences all number	9	1	2	0	0
Back pain
subjects affected / exposed	5 / 41 (12.20%)	2 / 37 (5.41%)	1 / 32 (3.13%)	1 / 41 (2.44%)	0 / 35 (0.00%)
occurrences all number	10	2	1	2	0
Musculoskeletal pain
subjects affected / exposed	3 / 41 (7.32%)	1 / 37 (2.70%)	1 / 32 (3.13%)	0 / 41 (0.00%)	0 / 35 (0.00%)
occurrences all number	3	2	1	0	0

More information

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Were there any global substantial amendments to the protocol? Yes

29 Jun 2018

One substantial protocol amendment was submitted for notification, to change the type of CRFs from electronic CRF to paper CRF.

10 Jan 2020

Amendment done to change the name of the study coordinator.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results:
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)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Proportion of Patients Showing a Reduction >= 50% in VAS for Pain at Day 30

Primary: Proportion of Patients Showing a Reduction >= 50% in VAS for Pain at Day 30

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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Clinical trials

Clinical Trial Results: 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)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Proportion of Patients Showing a Reduction >= 50% in VAS for Pain at Day 30

Primary: Proportion of Patients Showing a Reduction >= 50% in VAS for Pain at Day 30

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
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)