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Clinical Trial Results:
A DOUBLE-BLIND, RANDOMISED, PLACEBO-CONTROLLED, FOUR PARALLEL ARM, DOSE-FINDING STUDY TO EVALUATE THE EFFICACY, SAFETY, TOLERABILITY, AND PHARMACOKINETICS OF SINGLE INTRA-ARTICULAR INJECTIONS OF FASITIBANT IN PATIENTS WITH SYMPTOMATIC OSTEOARTHRITIS OF THE KNEE.

Summary
EudraCT number	2013-004999-35
Trial protocol	DE IT CZ
Global end of trial date	10 Feb 2015

Results information
Results version number	v1(current)
This version publication date	07 Aug 2016
First version publication date	07 Aug 2016
Other versions
Summary report(s)	CSR Synopsis

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

BKOS-04

ISRCTN number

US NCT number

NCT02205814

WHO universal trial number (UTN)

Sponsor organisation name

Menarini Ricerche S.p.A.

Sponsor organisation address

Via Sette Santi, 1, Florence, Italy, 50131

Public contact

Dr. Angela Capriati, Clinical Research, Menarini Ricerche S.p.A., 0039 05556809990, acapriati@menarini-ricerche.it

Scientific contact

Dr. Angela Capriati, Clinical Research, Menarini Ricerche S.p.A., 0039 05556809990, acapriati@menarini-ricerche.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

18 May 2015

Is this the analysis of the primary completion data?

Yes

Primary completion date

06 Jan 2015

Global end of trial reached?

Yes

Global end of trial date

10 Feb 2015

Was the trial ended prematurely?

Main objective of the trial

To evaluate fasitibant, given as single IA injection at three different doses versus placebo, as an efficacious symptom modifying treatment of knee OA.

Protection of trial subjects

Protection of trial subjects: If any event(s) related to the conduct of the study or the development of the IMP affects the safety of the study participants, the Sponsor and the Investigator will take appropriate urgent safety measures to protect the patients against any immediate hazard. The CAs and IRB/ECs will be informed forthwith about these new events and the measures taken. For patients participating in the study, Menarini Ricerche S.p.A. has stipulated an insurance policy in accordance with local regulatory requirements. Details on the insurance company, the insurance number and conditions will be made available to patients in the ICF and/or provided as a separate document, in accordance with national requirements. Fasitibant is intended to be administered intra-articular in the knee joint. By delivering the drug substance directly to the site of interest, optimum activity can be obtained. This allows minimizing the dose and also the risk of systemic side effects. In all completed clinical studies the local tolerability of treatment injection was very good, without any difference between fasitibant and placebo. As far as the placebo group is concerned, it is worth noting that a high placebo effect has been reported in clinical studies on osteoarthritis symptomatic treatment, with the highest efficacy rate for IA placebo administration. For this reason, the inclusion of a placebo arm is justified and aligned with regulatory guidelines, for drugs intended to treat osteoarthritis. Finally, the use of paracetamol/acetaminophen as rescue medication along the study, as recommended by guidelines on OA management, is intended to minimize the discomfort of patients who are allocated to non-efficacious doses of fasitibant, if any, or to placebo.

Background therapy

Evidence for comparator

Actual start date of recruitment

06 May 2014

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy, Ethical reason, Regulatory reason, Scientific research

Long term follow-up duration

3 Months

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 31

Country: Number of subjects enrolled

Czech Republic: 72

Country: Number of subjects enrolled

Germany: 324

Country: Number of subjects enrolled

Italy: 9

Worldwide total number of subjects

436

EEA total number of subjects

405

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)

206

From 65 to 84 years

230

85 years and over

Subject disposition

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Recruitment details

The first patient was screened on 28th April 2014. The first patient was randomised on 6th May 2014. The last patient completed the study on 6th January 2015. The study was conducted in 25 study sites in Czech Republic, Germany, Italy and US.

Screening details

A total of 645 patients entered a 2-week Screening period (including wash out); 209 of them were screen failed. One patient randomised to PLACEBO did not receive the study treatment (counted for ITT but not in safety population). Five patients received the study treatment without randomisation (not counted for ITT (n=431), but in safety population.

Period 1 title

Baseline

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Baseline Fasitibant Low Dose

Arm description

At Visit 2 immediately before randomisation to low dose of fasitibant

Arm type

Baseline

Investigational medicinal product name

not applicable

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intraarticular use

Dosage and administration details

not applicable for baseline group

Baseline Fasitibant Intermediate Dose

Arm description

At Visit 2 immediately before randomisation to intermediate dose of fasitibant

Arm type

Baseline

Investigational medicinal product name

not applicable

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intraarticular use

Dosage and administration details

not applicable for baseline group

Baseline Fasitibant High Dose

Arm description

At Visit 2 immediately before randomisation to high dose of fasitibant

Arm type

Baseline

Investigational medicinal product name

not applicable

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intraarticular use

Dosage and administration details

not applicable for baseline group

Baseline Placebo

Arm description

At Visit 2 immediately before randomisation to placebo

Arm type

Baseline

Investigational medicinal product name

not applicable

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intraarticular use

Dosage and administration details

not applicable for baseline group

Number of subjects in period 1	Baseline Fasitibant Low Dose	Baseline Fasitibant Intermediate Dose	Baseline Fasitibant High Dose	Baseline Placebo
Started	110	110	108	108
Completed	108	108	107	108
Not completed	2	2	1	0
Protocol deviation	2	2	1	-

Period 2 title

12 Week Post-Treatment Follow Up

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

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

Blinding implementation details

Eligible patients were randomised at the end of the 2-week run-in period and after rechecking eligibility criteria, as per treatment code by the IVRS/IWRS in accordance with the randomisation list. Double-blind conditions were secured by the identical appearance and viscosity of the fasitibant and placebo solutions. The blind remained in effect until the database was completed and locked.

Are arms mutually exclusive

Yes

Fasitibant Low Dose

Arm description

At Visit 2 (T0 – Randomisation and Treatment Administration) patients will receive one intra articular injection of fasitibant low dose and will be followed up for a period of 12 weeks post-treatment.

Arm type

Experimental

Investigational medicinal product name

Fasitibant

Investigational medicinal product code

MEN 16132

Other name

Fasitibant chloride bis-hydrochloride

Pharmaceutical forms

Solution for injection

Routes of administration

Intraarticular use

Dosage and administration details

At Visit 2 (T0 – Randomisation and Treatment Administration) patients will receive one intra articular injection of fasitibant 1 mg/mL (1 mL solution for IA injection) into the target knee.

Fasitibant Intermediate Dose

Arm description

At Visit 2 (T0 – Randomisation and Treatment Administration) patients will receive one intra articular injection of fasitibant intermediate dose and will be followed up for a period of 12 weeks post-treatment.

Arm type

Experimental

Investigational medicinal product name

Fasitibant

Investigational medicinal product code

MEN16132

Other name

Fasitibant chloride bis-hydrochloride

Pharmaceutical forms

Solution for injection

Routes of administration

Intraarticular use

Dosage and administration details

At Visit 2 (T0 – Randomisation and Treatment Administration) patients will receive one intra articular injection of fasitibant 2.5 mg/mL (1 mL solution for IA injection) into the target knee.

Fasitibant High Dose

Arm description

At Visit 2 (T0 – Randomisation and Treatment Administration) patients will receive one intra articular injection of fasitibant high dose and will be followed up for a period of 12 weeks post-treatment.

Arm type

Experimental

Investigational medicinal product name

Fasitibant

Investigational medicinal product code

MEN 16132

Other name

Fasitibant chloride bis-hydrochloride

Pharmaceutical forms

Solution for injection

Routes of administration

Intraarticular use

Dosage and administration details

At Visit 2 (T0 – Randomisation and Treatment Administration) patients will receive one intra articular injection of fasitibant 5 mg/mL (1 mL solution for IA injection) into the target knee.

Placebo

Arm description

At Visit 2 (T0 – Randomisation and Treatment Administration) patients will receive one intra articular injection of placebo and will be followed up for a period of 12 weeks post-treatment.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intraarticular use

Dosage and administration details

At Visit 2 (T0 – Randomisation and Treatment Administration) patients will receive one intra articular injection of placebo (1 mL solution for IA injection) into the target knee.

Number of subjects in period 2	Fasitibant Low Dose	Fasitibant Intermediate Dose	Fasitibant High Dose	Placebo
Started	108	108	107	108
Completed	108	108	107	108

Baseline characteristics

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Reporting group title

Baseline Fasitibant Low Dose

Reporting group description

At Visit 2 immediately before randomisation to low dose of fasitibant

Reporting group title

Baseline Fasitibant Intermediate Dose

Reporting group description

At Visit 2 immediately before randomisation to intermediate dose of fasitibant

Reporting group title

Baseline Fasitibant High Dose

Reporting group description

At Visit 2 immediately before randomisation to high dose of fasitibant

Reporting group title

Baseline Placebo

Reporting group description

At Visit 2 immediately before randomisation to placebo

Reporting group values	Baseline Fasitibant Low Dose	Baseline Fasitibant Intermediate Dose	Baseline Fasitibant High Dose	Baseline Placebo	Total
Number of subjects	110	110	108	108	436
Age categorical
Units: Subjects
In utero					0
Preterm newborn infants (gestational age < 37 wks)					0
Newborns (0-27 days)					0
Infants and toddlers (28 days-23 months)					0
Children (2-11 years)					0
Adolescents (12-17 years)					0
Adults (18-64 years)					0
From 65-84 years					0
85 years and over					0
Age continuous
Age, continuous
Units: years
arithmetic mean (standard deviation)	65.3 ± 7.61	63.2 ± 8.73	64.7 ± 8.43	64.4 ± 8.5	-
Gender categorical
Gender categorical
Units: Subjects
Female	62	72	64	66	264
Male	48	38	44	42	172
Ethnicity
Non Hispanic or Latino
Units: Subjects
Not Hispanic or Latino	109	109	107	106	431
Hispanic or Latino	1	1	1	2	5
BMI
BMI
Units: kg/m2
arithmetic mean (standard deviation)	27.1 ± 2.12	26.5 ± 2.83	27.1 ± 2.35	27 ± 2.6	-
WOMAC A
The validated Western Ontario and McMaster University questionnaire (WOMAC) was used to measure total knee pain choosing its visual analogue scale version (VAS). The WOMAC VA 3.1 A subscore (WOMAC A) ranges from 0 to 500 mm (summing up five VAS 0-100 mm) with higher scores indicating more pain.
Units: units on a scale
arithmetic mean (standard deviation)	286.5 ± 40.4	282.7 ± 40.08	278.3 ± 38.11	275.5 ± 39.81	-
WOMAC INDEX
The WOMAC VA 3.1 Index score (WOMAC INDEX) is the sum of WOMAC A (total pain), WOMAC B (stiffness) and WOMAC C (functional impairment) subscores. The WOMAC INDEX score ranges from 0 to 2400 mm, with higher scores indicating higher disease burden.
Units: units on a scale
arithmetic mean (standard deviation)	1321.5 ± 278.88	1275.4 ± 283.6	1282.6 ± 274.5	1293.5 ± 239.73	-
EQ VAS
The EQ visual analogue scale (EQ VAS) recorded the respondent’s self-rated health on a 20 cm vertical VAS with endpoints labelled ‘the best health you can imagine’ on top (equal to 100) and ‘the worst health you can imagine’ at the bottom (equal to 0).
Units: units on a scale
arithmetic mean (standard deviation)	63.1 ± 20.54	64.3 ± 17.21	67.4 ± 18.18	65.7 ± 19.47	-

End points

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Reporting group title

Baseline Fasitibant Low Dose

Reporting group description

At Visit 2 immediately before randomisation to low dose of fasitibant

Reporting group title

Baseline Fasitibant Intermediate Dose

Reporting group description

At Visit 2 immediately before randomisation to intermediate dose of fasitibant

Reporting group title

Baseline Fasitibant High Dose

Reporting group description

At Visit 2 immediately before randomisation to high dose of fasitibant

Reporting group title

Baseline Placebo

Reporting group description

At Visit 2 immediately before randomisation to placebo

Reporting group title

Fasitibant Low Dose

Reporting group description

Reporting group title

Fasitibant Intermediate Dose

Reporting group description

Reporting group title

Fasitibant High Dose

Reporting group description

Reporting group title

Placebo

Reporting group description

At Visit 2 (T0 – Randomisation and Treatment Administration) patients will receive one intra articular injection of placebo and will be followed up for a period of 12 weeks post-treatment.

Primary: Change in WOMAC A

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End point title

Change in WOMAC A

End point description

The validated Western Ontario and McMaster University questionnaire (WOMAC) was used to measure total knee pain choosing its visual analogue scale version (VAS). The WOMAC VA 3.1 A subscore (WOMAC A) ranges from 0 to 500 mm (summing up five VAS 0-100 mm) with higher scores indicating more pain.

End point type

Primary

End point timeframe

from baseline up to 2 weeks after randomisation

End point values	Fasitibant Low Dose	Fasitibant Intermediate Dose	Fasitibant High Dose	Placebo
Number of subjects analysed	108	108	107	108
Units: units on a scale
arithmetic mean (standard deviation)	-106.1 ± 101.88	-131.5 ± 96.41	-115.9 ± 104.61	117.2 ± 90.15

Mixed linear model for repeated measures

Statistical analysis description

Fourhundred evaluable patients were supposed to provide approximately 80% power in rejecting the null hypothesis of equality between any dose of fasitibant and placebo based on previous results and an overall significance level of 5% (two-sided).

Comparison groups

Fasitibant Low Dose v Fasitibant Intermediate Dose v Fasitibant High Dose v Placebo

Number of subjects included in analysis

431

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

P-value

< 0.05

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Notes
[1] - The primary efficacy variable was analysed on the ITT population. Multiplicity was adjusted using the Hochberg procedure. The continuous efficacy variable was analysed over time. The minimum efficacy was defined as at least 40% pain reduction over placebo (considered for sample size calculation).

Secondary: Change in WOMAC INDEX

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End point title

Change in WOMAC INDEX

End point description

The WOMAC VA 3.1 Index score (WOMAC INDEX) is the sum of WOMAC A (total pain), WOMAC B (stiffness) and WOMAC C (functional impairment) subscores. The WOMAC INDEX score ranges from 0 to 2400 mm, with higher scores indicating higher disease burden.

End point type

Secondary

End point timeframe

from baseline up to 6 weeks after randomisation

End point values	Fasitibant Low Dose	Fasitibant Intermediate Dose	Fasitibant High Dose	Placebo
Number of subjects analysed	108	108	107	108
Units: units on a scale
arithmetic mean (standard deviation)	-566.3 ± 525.63	-653.8 ± 516.31	-547.6 ± 522.37	-581.3 ± 503.37

Mixed linear model for repeated measures

Statistical analysis description

Comparison groups

Fasitibant Low Dose v Fasitibant Intermediate Dose v Fasitibant High Dose v Placebo

Number of subjects included in analysis

431

Analysis specification

Pre-specified

Analysis type

superiority ^[2]

P-value

< 0.05

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Notes
[2] - All secondary efficacy variables were analysed on the ITT population only. Multiplicity was adjusted using the Hochberg procedure. The continuous secondary efficacy variables were analysed over time and were treated in the same way as the primary efficacy variable with respective output.

Secondary: Responder Rate According to OMERACT-OARSI Criteria

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End point title

Responder Rate According to OMERACT-OARSI Criteria

End point description

Percentage of responders according to Outcome Measures in Rheumatology-Osteoarthritis Research Society International (OMERACT-OARSI) criteria. Patients with at least 50 % improvement in pain or in function scores are considered responders. Alternatively, patients are considered responders if they show at least 20% improvement in at least two of the following scores: pain, function and Patients's Global Assessment (PGA) scores.

End point type

Secondary

End point timeframe

from baseline up to 6 weeks after randomisation

End point values	Fasitibant Low Dose	Fasitibant Intermediate Dose	Fasitibant High Dose	Placebo
Number of subjects analysed	108	108	107	108
Units: percentage of responders
Week 1 after randomisation	52	57	64	56
Week 2 after randomisation	59	72	63	69
Week 4 after randomisation	66	72	65	67
Week 6 after randomisation	71	74	67	68

No statistical analyses for this end point

Secondary: Euro Quality of Life Questionnaire (EQ-5D-5L) Responder Rate

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End point title

Euro Quality of Life Questionnaire (EQ-5D-5L) Responder Rate

End point description

Response based on change ≥ 20 % from baseline for EQ-5D-5L index value

End point type

Secondary

End point timeframe

from baseline up to 6 weeks after randomisation

End point values	Fasitibant Low Dose	Fasitibant Intermediate Dose	Fasitibant High Dose	Placebo
Number of subjects analysed	108	108	107	108
Units: Percentage of Responders
Week 2 after randomisation	19	19	21	24
Week 6 after randomisation	23	28	25	21

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

For all patients receiving the study treatment (safety population, N=435), adverse event data were collected over a period of maximal 15 weeks (including the 12 week post-treatment period and the screening period up to a maximum of 3 weeks).

Adverse event reporting additional description

An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical trial subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

16.1

Reporting group title

Fasitibant Low Dose

Reporting group description

Patients receiving at least one single injection of low dose fasitibant

Reporting group title

Fasitibant Intermediate Dose

Reporting group description

Patients receiving at least one single injection of intermediate dose fasitibant

Reporting group title

Fasitibant High Dose

Reporting group description

Patients receiving at least one single injection of high dose fasitibant

Reporting group title

Placebo

Reporting group description

Patients receiving at least one single injection of placebo.

Serious adverse events	Fasitibant Low Dose	Fasitibant Intermediate Dose	Fasitibant High Dose	Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	2 / 110 (1.82%)	2 / 110 (1.82%)	2 / 108 (1.85%)	4 / 107 (3.74%)
number of deaths (all causes)	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0
Investigations
Hepatic enzyme increased
subjects affected / exposed	0 / 110 (0.00%)	0 / 110 (0.00%)	0 / 108 (0.00%)	1 / 107 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer female
subjects affected / exposed	1 / 110 (0.91%)	0 / 110 (0.00%)	0 / 108 (0.00%)	0 / 107 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Femur fracture
subjects affected / exposed	0 / 110 (0.00%)	0 / 110 (0.00%)	0 / 108 (0.00%)	1 / 107 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	0 / 110 (0.00%)	1 / 110 (0.91%)	0 / 108 (0.00%)	0 / 107 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Thoracic vertebral fracture
subjects affected / exposed	0 / 110 (0.00%)	1 / 110 (0.91%)	0 / 108 (0.00%)	0 / 107 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Hernia repair
subjects affected / exposed	0 / 110 (0.00%)	0 / 110 (0.00%)	1 / 108 (0.93%)	0 / 107 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Knee arthroplasty
subjects affected / exposed	0 / 110 (0.00%)	0 / 110 (0.00%)	0 / 108 (0.00%)	1 / 107 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Malignant breast lump removal
subjects affected / exposed	1 / 110 (0.91%)	0 / 110 (0.00%)	0 / 108 (0.00%)	0 / 107 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Inguinal hernia
subjects affected / exposed	0 / 110 (0.00%)	0 / 110 (0.00%)	1 / 108 (0.93%)	0 / 107 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Laryngeal oedema
subjects affected / exposed	1 / 110 (0.91%)	0 / 110 (0.00%)	0 / 108 (0.00%)	0 / 107 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 110 (0.00%)	0 / 110 (0.00%)	0 / 108 (0.00%)	1 / 107 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Urinary tract infection
subjects affected / exposed	0 / 110 (0.00%)	0 / 110 (0.00%)	1 / 108 (0.93%)	0 / 107 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Hypercalcaemia
subjects affected / exposed	0 / 110 (0.00%)	0 / 110 (0.00%)	0 / 108 (0.00%)	1 / 107 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Fasitibant Low Dose	Fasitibant Intermediate Dose	Fasitibant High Dose	Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	28 / 110 (25.45%)	46 / 110 (41.82%)	36 / 108 (33.33%)	44 / 107 (41.12%)
Investigations
Ligament sprain
subjects affected / exposed	0 / 110 (0.00%)	2 / 110 (1.82%)	0 / 108 (0.00%)	0 / 107 (0.00%)
occurrences all number	0	2	0	0
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 110 (0.00%)	0 / 110 (0.00%)	2 / 108 (1.85%)	0 / 107 (0.00%)
occurrences all number	0	0	2	0
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	2 / 110 (1.82%)	0 / 110 (0.00%)	0 / 108 (0.00%)	1 / 107 (0.93%)
occurrences all number	2	0	0	1
Vascular disorders
Hypertension
subjects affected / exposed	2 / 110 (1.82%)	0 / 110 (0.00%)	1 / 108 (0.93%)	0 / 107 (0.00%)
occurrences all number	2	0	1	0
Nervous system disorders
Headache
subjects affected / exposed	3 / 110 (2.73%)	3 / 110 (2.73%)	1 / 108 (0.93%)	2 / 107 (1.87%)
occurrences all number	4	4	1	2
General disorders and administration site conditions
Injection site haematoma
subjects affected / exposed	0 / 110 (0.00%)	2 / 110 (1.82%)	0 / 108 (0.00%)	1 / 107 (0.93%)
occurrences all number	0	2	0	1
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 110 (0.00%)	2 / 110 (1.82%)	0 / 108 (0.00%)	2 / 107 (1.87%)
occurrences all number	0	2	0	2
Diarrhea
subjects affected / exposed	1 / 110 (0.91%)	1 / 110 (0.91%)	2 / 108 (1.85%)	3 / 107 (2.80%)
occurrences all number	1	1	2	3
Toothache
subjects affected / exposed	1 / 110 (0.91%)	1 / 110 (0.91%)	1 / 108 (0.93%)	2 / 107 (1.87%)
occurrences all number	1	2	1	3
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	4 / 110 (3.64%)	7 / 110 (6.36%)	5 / 108 (4.63%)	8 / 107 (7.48%)
occurrences all number	6	7	6	8
Back pain
subjects affected / exposed	2 / 110 (1.82%)	4 / 110 (3.64%)	5 / 108 (4.63%)	6 / 107 (5.61%)
occurrences all number	2	5	5	6
Joint swelling
subjects affected / exposed	1 / 110 (0.91%)	1 / 110 (0.91%)	1 / 108 (0.93%)	2 / 107 (1.87%)
occurrences all number	1	1	1	2
Muscle spasms
subjects affected / exposed	1 / 110 (0.91%)	0 / 110 (0.00%)	2 / 108 (1.85%)	1 / 107 (0.93%)
occurrences all number	1	0	2	1
Musculoskeletal pain
subjects affected / exposed	0 / 110 (0.00%)	2 / 110 (1.82%)	0 / 108 (0.00%)	0 / 107 (0.00%)
occurrences all number	0	2	0	0
Pain in extremity
subjects affected / exposed	2 / 110 (1.82%)	0 / 110 (0.00%)	1 / 108 (0.93%)	0 / 107 (0.00%)
occurrences all number	2	0	1	0
Infections and infestations
Gastroenteritis
subjects affected / exposed	0 / 110 (0.00%)	2 / 110 (1.82%)	0 / 108 (0.00%)	0 / 107 (0.00%)
occurrences all number	0	2	0	0
Nasopharyngitis
subjects affected / exposed	4 / 110 (3.64%)	17 / 110 (15.45%)	11 / 108 (10.19%)	13 / 107 (12.15%)
occurrences all number	4	18	11	13
Rhinitis
subjects affected / exposed	2 / 110 (1.82%)	1 / 110 (0.91%)	2 / 108 (1.85%)	0 / 107 (0.00%)
occurrences all number	2	1	2	0
Urinary tract infection
subjects affected / exposed	3 / 110 (2.73%)	1 / 110 (0.91%)	2 / 108 (1.85%)	3 / 107 (2.80%)
occurrences all number	3	1	2	3

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Were there any global substantial amendments to the protocol? Yes

26 Feb 2014

There was one substantial amendment to study protocol version 1.0 (dated 09DEC2013) in order to accomplish all changes that were requested by the competent authorities for study approval. Main changes are summarised below: 1) The duration of the follow up for safety evaluation of fasitibant was extended up to 12 weeks after treatment administration. 2) The obligation to adopt the double barrier contraception method was integrated in the corresponding Inclusion Criterion. 3) Additional cardiac safety monitoring was included (12-lead ECG prior to and 2 hours post intraarticular injection) in the protocol. 4) The exclusion of patients taking any concomitant medications that are CYP3A4 substrates and/or moderate or strong CYP3A4 inhibitors starting from 4 weeks prior to randomisation and along study duration was added as Exclusion Criterion, considering the potential of fasitibant to be a time dependent CYP 3A4 inhibitor. Patients taking weak CYP3A4 inhibitors could be included in the study. Medications metabolised by CYP3A4 as well as grapefruit juice were included in the prohibited medication/food restrictions required by the protocol. All above changes were implemented in the study protocol version 2.0 (dated 26 FEB 2014).

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 DOUBLE-BLIND, RANDOMISED, PLACEBO-CONTROLLED, FOUR PARALLEL ARM, DOSE-FINDING STUDY TO EVALUATE THE EFFICACY, SAFETY, TOLERABILITY, AND PHARMACOKINETICS OF SINGLE INTRA-ARTICULAR INJECTIONS OF FASITIBANT IN PATIENTS WITH SYMPTOMATIC OSTEOARTHRITIS OF THE KNEE.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change in WOMAC A

Primary: Change in WOMAC A

Secondary: Change in WOMAC INDEX

Secondary: Change in WOMAC INDEX

Secondary: Responder Rate According to OMERACT-OARSI Criteria

Secondary: Responder Rate According to OMERACT-OARSI Criteria

Secondary: Euro Quality of Life Questionnaire (EQ-5D-5L) Responder Rate

Secondary: Euro Quality of Life Questionnaire (EQ-5D-5L) Responder Rate

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical trials

Clinical Trial Results: A DOUBLE-BLIND, RANDOMISED, PLACEBO-CONTROLLED, FOUR PARALLEL ARM, DOSE-FINDING STUDY TO EVALUATE THE EFFICACY, SAFETY, TOLERABILITY, AND PHARMACOKINETICS OF SINGLE INTRA-ARTICULAR INJECTIONS OF FASITIBANT IN PATIENTS WITH SYMPTOMATIC OSTEOARTHRITIS OF THE KNEE.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change in WOMAC A

Primary: Change in WOMAC A

Secondary: Change in WOMAC INDEX

Secondary: Change in WOMAC INDEX

Secondary: Responder Rate According to OMERACT-OARSI Criteria

Secondary: Responder Rate According to OMERACT-OARSI Criteria

Secondary: Euro Quality of Life Questionnaire (EQ-5D-5L) Responder Rate

Secondary: Euro Quality of Life Questionnaire (EQ-5D-5L) Responder Rate

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A DOUBLE-BLIND, RANDOMISED, PLACEBO-CONTROLLED, FOUR PARALLEL ARM, DOSE-FINDING STUDY TO EVALUATE THE EFFICACY, SAFETY, TOLERABILITY, AND PHARMACOKINETICS OF SINGLE INTRA-ARTICULAR INJECTIONS OF FASITIBANT IN PATIENTS WITH SYMPTOMATIC OSTEOARTHRITIS OF THE KNEE.