Assess the Blood-Oxygen-Level-Dependent (BOLD) Signal Changes in the Brain by Paracetamol as Measured by Functional Magnetic Resonance Imaging (fMRI) in Subjects With Osteoarthritis (OA)

A Randomised, Double-blind, Evaluation of the Effects of Paracetamol on the BOLD fMRI Response to Painful Stimuli in Subjects With Osteoarthritis

Status

Completed

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01105936

Enrollment

Registered

2010-04-19

Start date

2010-09-01

Completion date

2011-08-01

Last updated

2017-06-21

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Osteoarthritis, Knee

Keywords

osteoarthritis, pain, paracetamol, Blood-Oxygen-Level-Dependent functional magnetic resonance imaging

Brief summary

Blood-Oxygen-Level-Dependent (BOLD) responses to painful mechanical stimulation of the OA knee following treatment with four consecutive doses (at 8 hour intervals) on giving sustained released paracetamol treatment or placebo will be compared. The fMRI and pain assessments will occur approximately 2-5 hours after taking the final dose.

Detailed description

The objective of this study is to investigate if functional magnetic response imaging (fMRI) can detect the effects of a known pain medicine at over-the-counter doses in people with osteoarthritis (OA) of the knee. The fMRI is a harmless and painless technique that is used in the current study to collect images of brain activity to see if is changed when feeling pain. In this study, BOLD response to mechanical stimulation via pressure stimuli applied to the tibio-femoral joint and patello-femoral in participants with knee OA following four treatment doses of any of three treatment will be compared.

Interventions

DRUGParacetamol

665 mg sustained release paracetamol caplets

DRUGPlacebo

Placebo caplets

Study design

Allocation

RANDOMIZED

Intervention model

CROSSOVER

Primary purpose

BASIC_SCIENCE

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

ALL

Age

45 Years to No maximum

Healthy volunteers

Inclusion criteria

* Diagnosis of osteoarthritis of at least one knee for 3 months * Male or female at least 45 years of age * Score a minimum of 4 out of 10 on the numerical pain rating and a maximum of 8 at screening

Exclusion criteria

* If female, is pregnant, lactating, or breast feeding * Has secondary cause of knee arthritis * Lower extremity surgery in the last 6 months * Prior injury in the last twelve months to the index knee * Used any analgesics (NSAIDs, COX2 inhibitor, etc) within 5 half lives of study start * Recently used oral or injected glucocorticoids

Design outcomes

Primary

Measure	Time frame	Description
Blood Oxygen Level-Dependent (BOLD) Response in the Tibio-femoral Joint of Knee Osteoarthritis (OA): [BOLD (T-f)]	Baseline to 2-5 hours post last dose administration	BOLD response to painful pressure stimuli was evaluated using fMRI. Voxel-wise BOLD scores were reported on a Z-scale (Gaussian,mean=0,SD=1); range -3 (worst score, lowest connectivity) to +3 (best score, highest connectivity). The software derived scores compared the intensity reading in the region to a template, specifically the Montreal Neurological Institute (MNI) Echo-Planar Image (EPI) template. The template provides, for each region, expected (mean/median) intensity for that region, along with expected variation. The BOLD score on the Z-scale represents how far the actual measured intensity is from the expected in the template. A score of 0 would correspond to the mean/median, a score of 1.65 would represent the 90-percentile, -1.65 the 10-percentile, and so on, according to a standard normal distribution.

Secondary

Measure	Time frame	Description
Subjective Numerical Rating Scale (NRS) Response for Treatment Effect on OA Knee Before Stimulation: [NRS (TRT)]	Baseline and post-dose before stimulus	Subjective NRS response for each participant was calculated as difference of pre-treatment NRS pain assessment before stimulus and post-treatment NRS pain assessment before stimulus. NRS responses was based on an 11 scale rating (0-10), with 0 corresponding to No Pain and 10 corresponding to Extreme Pain or Pain as bad as you can imagine.
Subjective NRS Response for Treatment Effect on Tibio-femoral Stimulation Prior the fMRI Scan: [NRS (T-f Pre-scan)]	Baseline and post-dose pre-scan after stimulus	Subjective NRS response was calculated for each participant as difference of pre-treatment pain assessment after stimulus and post-treatment pre-scan pain assessment after stimulus on tibio-femoral joint. NRS responses was based on an 11 scale rating (0-10), with 0 corresponding to No Pain and 10 corresponding to Extreme Pain or Pain as bad as you can imagine.
BOLD Response in the Patello-femoral Joint of Knee Osteoarthritis: [BOLD (P-f)]	Baseline to 2-5 hours post last dose administration	BOLD response to painful pressure stimuli was evaluated using fMRI. Voxel-wise BOLD scores were reported on a Z-scale (Gaussian,mean=0,SD=1); range -3 (worst score, lowest connectivity) to +3 (best score, highest connectivity). The software derived scores compared the intensity reading in the region to a template, specifically the Montreal Neurological Institute (MNI) Echo-Planar Image (EPI) template. The template provides, for each region, expected (mean/median) intensity for that region, along with expected variation. The BOLD score on the Z-scale represents how far the actual measured intensity is from the expected in the template. A score of 0 would correspond to the mean/median, a score of 1.65 would represent the 90-percentile, -1.65 the 10-percentile, and so on, according to a standard normal distribution
Subjective NRS Response for Treatment Effect on Tibio-femoral Stimulation After the fMRI Scan: [NRS (T-f Post-scan)]	Baseline and post-dose post-scan after stimulus	Subjective NRS response for treatment effect on tibio-femoral stimulus after the fMRI scan was calculated for each participant as difference of pre-treatment pain assessment after stimulus and post-treatment post-scan pain assessment after stimulus on tibio-femoral. NRS responses was based on an 11 scale rating (0-10), with 0 corresponding to No Pain and 10 corresponding to Extreme Pain or Pain as bad as you can imagine.
Subjective NRS Response for Treatment Effect on Patello-femoral Stimulation After the fMRI Scan: [NRS (P-f Post-scan)]	Baseline and post-dose post-scan after stimulus	Subjective NRS response for each participant for treatment effect on tibio-femoral stimulus after the fMRI scan was calculated as difference of pre-treatment pain assessment after stimulus and post-treatment post-scan pain assessment after stimulus on patello-femoral. NRS responses was based on an 11 scale rating (0-10), with 0 corresponding to No Pain and 10 corresponding to Extreme Pain or Pain as bad as you can imagine.
Subjective NRS Response for Treatment Effect on Patello-femoral Stimulation Prior the fMRI Scan: [NRS (P-f Pre-scan)]	Baseline and post-dose pre-scan after stimulus	Subjective NRS response was calculated for each participant as difference of pre-treatment pain assessment after stimulus and post-treatment pre-scan pain assessment after stimulus on patello-femoral. NRS responses was based on an 11 scale rating (0-10), with 0 corresponding to No Pain and 10 corresponding to Extreme Pain or Pain as bad as you can imagine.

Countries

Spain

Participant flow

Recruitment details

Study was conducted at a single centre in Spain.

Pre-assignment details

Out of 33 screened participants, 31 were randomized, while 2 participants were considered as screen failures

Participants by arm

Arm	Count
Total Participants for Baseline Measurement All randomized participants except one were evaluated for baseline measures. One participant had misallocated treatments that could not be determined. Therefore, this participant was excluded from all populations including safety.	30
Total	30

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG003
Period 1	Adverse Event	0	0	1
Period 2	Adverse Event	1	0	0
Period 3	Protocol Violation	0	2	0

Baseline characteristics

Characteristic	Total Participants for Baseline Measurement
Age, Customized Years	68.5 Years STANDARD_DEVIATION 7.97
Sex: Female, Male Female	26 Participants
Sex: Female, Male Male	4 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —
other Total, other adverse events	3 / 29	3 / 28	2 / 30
serious Total, serious adverse events	0 / 29	0 / 28	0 / 30

Outcome results

Primary

Blood Oxygen Level-Dependent (BOLD) Response in the Tibio-femoral Joint of Knee Osteoarthritis (OA): [BOLD (T-f)]

BOLD response to painful pressure stimuli was evaluated using fMRI. Voxel-wise BOLD scores were reported on a Z-scale (Gaussian,mean=0,SD=1); range -3 (worst score, lowest connectivity) to +3 (best score, highest connectivity). The software derived scores compared the intensity reading in the region to a template, specifically the Montreal Neurological Institute (MNI) Echo-Planar Image (EPI) template. The template provides, for each region, expected (mean/median) intensity for that region, along with expected variation. The BOLD score on the Z-scale represents how far the actual measured intensity is from the expected in the template. A score of 0 would correspond to the mean/median, a score of 1.65 would represent the 90-percentile, -1.65 the 10-percentile, and so on, according to a standard normal distribution.

Time frame: Baseline to 2-5 hours post last dose administration

Population: Intention-to-treat (ITT) population: all participants per period who received at least one treatment and had at least one post-baseline efficacy assessment. Missing data was not imputed.

Arm	Measure	Value (MEAN)
Paracetamol 665 mg	Blood Oxygen Level-Dependent (BOLD) Response in the Tibio-femoral Joint of Knee Osteoarthritis (OA): [BOLD (T-f)]	NA Z-score
Placebo	Blood Oxygen Level-Dependent (BOLD) Response in the Tibio-femoral Joint of Knee Osteoarthritis (OA): [BOLD (T-f)]	NA Z-score
No Treatment	Blood Oxygen Level-Dependent (BOLD) Response in the Tibio-femoral Joint of Knee Osteoarthritis (OA): [BOLD (T-f)]	NA Z-score

Secondary