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Clinical Trial Results:
NEUORIMPA - Intraarticular Application of Opioids in Chronic Arthritis of the knee joint

Summary
EudraCT number	2015-000538-31
Trial protocol	DE
Global end of trial date	27 Aug 2021

Results information
Results version number	v1(current)
This version publication date	20 Mar 2023
First version publication date	20 Mar 2023
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

Neuroimpa2015

ISRCTN number

US NCT number

NCT02967302

WHO universal trial number (UTN)

Other trial identifiers

DRKS: DRKS00011113

Sponsor organisation name

Charité - Universitätsmedizin Berlin

Sponsor organisation address

Charitéplatz 1, Berlin, Germany, 10117

Public contact

PD Dr. Hildrun Haibel , Dep. of Rheumatology, Charité Campus Benjamin Franklin (CBF), Hindenburgdamm 30, 12203 Berlin , +49 030 8445 4547, hildrun.haibel@charite.de

Scientific contact

PD Dr. Hildrun Haibel , Dep. of Rheumatology, Charité Campus Benjamin Franklin (CBF), Hindenburgdamm 30, 12203 Berlin , +49 030 8445 4547, hildrun.haibel@charite.de

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

17 Jan 2022

Is this the analysis of the primary completion data?

Yes

Primary completion date

27 Aug 2021

Global end of trial reached?

Yes

Global end of trial date

27 Aug 2021

Was the trial ended prematurely?

Main objective of the trial

To investigate pain and inflammatory parameters (cytokines, immune cells) in knee joint tissue of chronic arthritis pa-tients following intraarticular (i.a.) injections of morphine, a standard steroid or placebo. The primary hypothesis is that i.a. morphine results in sig-nificantly lower pain scores and supplemental analgesic consumption than placebo during the first week after injec-tion, an efficacy comparable to standard i.a. steroid (tri-amcinolone) medication. Primary efficacy endpoint: Reduction of pain intensity (on a 100mm VAS) at 8 a.m. on day 7 compared to baseline.

Protection of trial subjects

The study was conducted according to the ethical principles of the Declaration of Helsinki. Daily activities, intensity and quality of pain are monitored for 2 weeks after intervention. Biopsies and synovial fluid aspiration are repeated after 7 days. Supplemental DMARDs are maintained at a stable dosage. Rescue medication: Patients have access to supplemental oral diclofenac (up to 150mg/day) or tramadol (up to 100 mg).

Background therapy

Patients with chronic inflammatory arthritis (e.g. rheumatoid arthritis; RA) or inflammatory exacerbations of chronic degenerative joint diseases (e.g. osteoarthritis; OA) suffer from recurrent pain, restricted function and reduction of daily activities. Such diseases are difficult to treat and lead to job loss, disability, premature retirement and increased compensatory expenses. Current standard treatments with nonsteroidal antiinflammatory drugs (NSAIDs), steroids or disease-modifying anti-rheumatic drugs (DMARDs) (e.g. methotrexate, biologicals) are partially effective , but can produce severe side effects (gastrointestinal ulcers, bleeding, thromboembolic complications, nephrotoxicity, hepatotoxicity, cartilage degeneration; Cushing’s syndrome, infections) .A novel approach without such complications is the activation of peripheral opioid receptors, e.g. by i.a. application of small, systemically inactive doses of morphine. In a large number (> 60) of published randomized controlled trials (RCT), we and others have shown that i.a. morphine produces significant analgesia in acute postoperative pain with similar efficacy to local anesthetics or steroids without systemic or local side effects .

Evidence for comparator

Actual start date of recruitment

06 Oct 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Germany: 93

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

Patients were recruited at department of rheumatology , Charity, from October 6th 2015 to 27th August 2021.

Screening details

114 patients were screened. 93 patients were randomised.

Period 1 title

Treatment + follow up (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Carer

Are arms mutually exclusive

Yes

placebo

Arm description

patient recieved i.a. injection 5ml of 0.9 % NaCl

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Injection

Dosage and administration details

0.9 % NaCl (5 ml; placebo) were i.a injected

Morphin

Arm description

patients received i.a. morphine (3 mg/5 ml)

Arm type

Experimental

Investigational medicinal product name

Morphinsulfat

Investigational medicinal product code

SUB14597MIG

Other name

Morphine Hexal

Pharmaceutical forms

Solution for injection

Routes of administration

Injection

Dosage and administration details

morphine (3 mg/5 ml) was i.a. injected

TRIAMCINOLONE

Arm description

triamcinolone for benchmarking to current active standard medication were i.a. injected

Arm type

Active comparator

Investigational medicinal product name

TRIAMCINOLONACETONID

Investigational medicinal product code

SUB41525

Other name

Triam 40 mg Lichtenstein

Pharmaceutical forms

Solution for injection

Routes of administration

Injection

Dosage and administration details

5ml (40 mg/ml) TRIAMCINOLONACETONID were i.a injected

Number of subjects in period 1	placebo	Morphin	TRIAMCINOLONE
Started	18	35	40
Completed	18	33	38
Not completed	0	2	2
Consent withdrawn by subject	-	1	-
no more interest	-	-	1
Lost to follow-up	-	1	1

Baseline characteristics

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Reporting group title

placebo

Reporting group description

patient recieved i.a. injection 5ml of 0.9 % NaCl

Reporting group title

Morphin

Reporting group description

patients received i.a. morphine (3 mg/5 ml)

Reporting group title

TRIAMCINOLONE

Reporting group description

triamcinolone for benchmarking to current active standard medication were i.a. injected

Reporting group values	placebo	Morphin	TRIAMCINOLONE	Total
Number of subjects	18	35	40	93
Age categorical
Units: Subjects
In utero	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0
Newborns (0-27 days)	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0
Children (2-11 years)	0	0	0	0
Adolescents (12-17 years)	0	0	0	0
Adults (18-64 years)	10	21	23	54
From 65-84 years	8	14	17	39
85 years and over	0	0	0	0
Age continuous
Units: years
arithmetic mean (standard deviation)	59.33 ± 14.56	59.37 ± 13.07	57.35 ± 15.32	-
Gender categorical
Units: Subjects
Female	11	16	21	48
Male	7	19	19	45
Height
Units: cm
arithmetic mean (standard deviation)	173.22 ± 9.79	172.6 ± 9.22	172.93 ± 10.98	-
Weight
Units: kg
arithmetic mean (standard deviation)	81.39 ± 20.44	85.11 ± 15.14	81.98 ± 14.74	-
CRP
Units: mg/l
arithmetic mean (standard deviation)	2.8 ± 2.67	5.69 ± 6.26	8.01 ± 14.34	-
VAS Pain last 7 days
Units: mm
arithmetic mean (standard deviation)	64 ± 14.78	65.6 ± 16.62	61.9 ± 13.15	-

End points

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Reporting group title

placebo

Reporting group description

patient recieved i.a. injection 5ml of 0.9 % NaCl

Reporting group title

Morphin

Reporting group description

patients received i.a. morphine (3 mg/5 ml)

Reporting group title

TRIAMCINOLONE

Reporting group description

triamcinolone for benchmarking to current active standard medication were i.a. injected

Primary: difference of VAS pain intensity on day 7 compared to baseline

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End point title

difference of VAS pain intensity on day 7 compared to baseline

End point description

In the first step, superiority of the experimental treatment vs. the placebo arm was tested (one sided test, type 1 error = 0.025). If this test was not significant, the procedure terminates and the result of the study was negative. In case of significance, a noninferiority test vs. the standard therapy was performed (one sided test, type 1 error = 0.025). A linear model including baseline as a continuous covariate was used for both steps of testing. In a sensitivity analysis, supplementary analgesic medication was included as an additional continuous covariate We expected that the adjustment of baseline as covariate will decrease the error term. Therefore, we did not anticipate less power due to the reduction of degrees of freedom by one of the error terms.

End point type

Primary

End point timeframe

from baseline to week 1

End point values	placebo	Morphin	TRIAMCINOLONE
Number of subjects analysed	18	33	38
Units: mm
arithmetic mean (standard error)	-19.83 ± 6.33	-22.85 ± 4.18	-37.69 ± 3.45

Attachments

primary-secundary-endpoints_NEUROIMPA

Differences VAS at 8 a.m on day 7/baseline

Comparison groups

Morphin v TRIAMCINOLONE v placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.025

Method

t-test, 2-sided

Parameter type

Mean difference (net)

Confidence interval

sides

2-sided

lower limit

upper limit

Variability estimate

Standard error of the mean

Adverse events

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Timeframe for reporting adverse events

overall study

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

Reporting group title

Morphine

Reporting group description

Reporting group title

Triamcinolone

Reporting group description

Reporting group title

Placebo

Reporting group description

Serious adverse events	Morphine	Triamcinolone	Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	0 / 22 (0.00%)
number of deaths (all causes)	0	0	0
number of deaths resulting from adverse events	0	0	0

Frequency threshold for reporting non-serious adverse events: 1%

Non-serious adverse events	Morphine	Triamcinolone	Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	12 / 45 (26.67%)	14 / 45 (31.11%)	5 / 22 (22.73%)
Injury, poisoning and procedural complications
Haematoma
subjects affected / exposed	1 / 45 (2.22%)	0 / 45 (0.00%)	1 / 22 (4.55%)
occurrences all number	2	0	1
pain at site of injection
subjects affected / exposed	0 / 45 (0.00%)	1 / 45 (2.22%)	0 / 22 (0.00%)
occurrences all number	0	1	0
Vascular disorders
Hypertension/ hypertensive crisis
subjects affected / exposed	3 / 45 (6.67%)	0 / 45 (0.00%)	0 / 22 (0.00%)
occurrences all number	3	0	0
Surgical and medical procedures
elective stomache operation
subjects affected / exposed	1 / 45 (2.22%)	0 / 45 (0.00%)	0 / 22 (0.00%)
occurrences all number	1	0	0
Nervous system disorders
Headache
subjects affected / exposed	0 / 45 (0.00%)	2 / 45 (4.44%)	1 / 22 (4.55%)
occurrences all number	0	2	1
General disorders and administration site conditions
tiredness
subjects affected / exposed	1 / 45 (2.22%)	1 / 45 (2.22%)	0 / 22 (0.00%)
occurrences all number	1	1	0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	2 / 45 (4.44%)	2 / 45 (4.44%)	1 / 22 (4.55%)
occurrences all number	2	2	1
Gastrointestinal disorders
Gastrointestinal disorder
subjects affected / exposed	1 / 45 (2.22%)	1 / 45 (2.22%)	0 / 22 (0.00%)
occurrences all number	1	1	0
Skin and subcutaneous tissue disorders
Exanthema on feet
subjects affected / exposed	0 / 45 (0.00%)	1 / 45 (2.22%)	0 / 22 (0.00%)
occurrences all number	0	1	0
Psychiatric disorders
hyperventilation
subjects affected / exposed	1 / 45 (2.22%)	0 / 45 (0.00%)	0 / 22 (0.00%)
occurrences all number	1	0	0
exitement
subjects affected / exposed	0 / 45 (0.00%)	1 / 45 (2.22%)	0 / 22 (0.00%)
occurrences all number	0	1	0
sleeplessness
subjects affected / exposed	0 / 45 (0.00%)	1 / 45 (2.22%)	0 / 22 (0.00%)
occurrences all number	0	1	0
Infections and infestations
Upper respiratory tract infection
subjects affected / exposed	4 / 45 (8.89%)	2 / 45 (4.44%)	1 / 22 (4.55%)
occurrences all number	5	3	1
Urinary tract infection
subjects affected / exposed	3 / 45 (6.67%)	1 / 45 (2.22%)	1 / 22 (4.55%)
occurrences all number	3	1	1
Gastroenteritis
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 22 (4.55%)
occurrences all number	0	0	1
herpes labialis
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)	1 / 22 (4.55%)
occurrences all number	0	0	1
Nail bed infection
subjects affected / exposed	0 / 45 (0.00%)	1 / 45 (2.22%)	0 / 22 (0.00%)
occurrences all number	0	1	0
elevated ESR
subjects affected / exposed	0 / 45 (0.00%)	1 / 45 (2.22%)	0 / 22 (0.00%)
occurrences all number	0	1	0

More information

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Were there any global substantial amendments to the protocol? Yes

24 Sep 2015

Deletion of the inclusion criterion Maximum weight 90 kg

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:
NEUORIMPA - Intraarticular Application of Opioids in Chronic Arthritis of the knee joint

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: difference of VAS pain intensity on day 7 compared to baseline

Primary: difference of VAS pain intensity on day 7 compared to baseline

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical trials

Clinical Trial Results: NEUORIMPA - Intraarticular Application of Opioids in Chronic Arthritis of the knee joint

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: difference of VAS pain intensity on day 7 compared to baseline

Primary: difference of VAS pain intensity on day 7 compared to baseline

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
NEUORIMPA - Intraarticular Application of Opioids in Chronic Arthritis of the knee joint