lIfestyle iNterventionS for PaIn ReliEf (INSPIRE)

Molecular Signatures of Endocannabinoid Induced Pain Relief in Humans: Lifestyle Interventions, Systemic and Localised Changes

Status

Completed

Phases

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT05670314

Acronym

INSPIRE

Enrollment

117

Registered

2023-01-04

Start date

2022-05-01

Completion date

2025-02-25

Last updated

2025-09-16

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

Conditions

Osteoarthritis, Knee

Brief summary

This is a 2x2 factorial design randomised controlled trial in which participants with knee pain will be grouped into the diet intervention, exercise intervention, diet and exercise intervention or placebo arm. The study involves intake of dietary supplements and performing routine exercises which are commonly used and are not pharmacological agents. N= 117. 2x2 intervention with individuals per block: placebo (n=27), diet only (n=26), exercise only (n=40), diet + exercise (n=24)

Interventions

DIETARY_SUPPLEMENTInulin Fibre supplement

20g/ day. Inulin is easily dissolvable in liquid and can be incorporated into the usual diet - by adding to water, juice, smoothies, cereal, yogurt etc.

DIETARY_SUPPLEMENTMaltodextrin (Placebo)

10g/ day which can be consumed by adding to breakfast cereal/ smoothie/ yogurt or drink of choice

BEHAVIORALExercise

Joint Academy An app-based exercises platform (Joint Academy®) will be used as an intervention given to the treatment arm. The programme consists of a mixture of open and close chain exercises, a combination of concentric, eccentric and focusing on the global strength of legs including the muscles around the hips and knee joints as well as balance enhancement exercises.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

BASIC_SCIENCE

Masking

DOUBLE (Subject, Investigator)

Masking description

Randomisation will be performed using an online software (sealedenvelope.com). The inulin vs placebo allocation will be double blinded. The exercise part of the intervention will not be blinded

Intervention model description

2x2 intervention with individuals per block: placebo (n=27), diet only (n=26), exercise only (n=40), diet + exercise (n=24)

Eligibility

Sex/Gender

ALL

Age

19 Years to No maximum

Healthy volunteers

Yes

Inclusion criteria

* Participants with any pain in or around a knee on most days for more than 3 months * Participant is willing and able to give informed consent for participation in the study * Participant eligibility includes those aged \>18 years who have a body mass index (BMI) between 18.5 and 39.9 kg/m2

Exclusion criteria

The participant may not enter the study if ANY of the following apply: * Have psychosocial or gastrointestinal (e.g. malabsorptive conditions such as IBS/IBD, coeliac) * Are taking the following medications: immunosuppressants, anticoagulants, amiodarone and/or perhexiline * Are currently following or anticipated to commence a specialised commercially available weight loss diet and/or program * Pregnant or breast feeding * History or current psychiatric illness * History or current neurological condition (e.g. epilepsy) * Those undergoing revision, having severe hip OA, inflammatory arthropathies * Diagnosed non-OA cause of knee pain (e.g. rheumatoid arthritis) * Neuropathy or diabetes mellitus * Having taken part in a research study in the last 3 months involving invasive procedures or an inconvenience allowance (this must remain for ALL UoN FMHS UREC approved studies)

Design outcomes

Primary

Measure	Time frame	Description
Change in Numerical Rate Score (NRS) for Pain	Baseline and 6 weeks	The Numerical Rate Score (NRS) will be used to assess the changes in the level of pain in response to the intervention between baseline and follow-up. Participants reported their pain on a scale ranging from 0 to 10, where 0 represents no pain and 10 the worst pain imaginable.

Secondary

Measure	Time frame	Description
Change in Functional Outcome Timed-up and go (TUG)	Baseline and 6 weeks	Time in seconds to stand up, walk 3m, return, and sit. Average of 3 trials at baseline and follow-up (at the end of 6 weeks).
Change in Functional Outcome Grip Strength	Baseline and 6 weeks	Measured with dynamometer; average of 3 trials on dominant hand in seated position with participant applying as much grip pressure as possible on the dynamometer. The maximum reading (kg) in taken for each repetition.
Change in Pain Sensitisation Outcome Temporal Summation (TS)	Baseline and 6 weeks	Pain sensitisation will be measured using quantitative sensory testing (QST) to assess any changes in pain sensitisation indices from at baseline to follow-up. QST is a non-invasive method to assess pain sensitivity using standardised stimuli like mechanical pressure or sharpness. We used the QST modality temporal summation (TS). TS assesses sensitivity to sharpness by applying a brief pinprick stimulus (256 mN Pinprick; MRC-Systems, Heidelberg, Germany) to the skin with higher ratings potentially suggesting increased spinal cord pain sensitivity. A single stimulus was applied to the rectus femoris (5cm above the mid-point of the patella of the most painful knee), followed by 10 repetitive stimuli at 1/s. Participants rated pain/sharpness intensity on a 0-10 Visual Analogue Scale after both the single and the average of the repeated stimuli. Each test was performed twice, with a 2-minute break between repetitions and the average was taken.
Changes in Pain Sensitisation Outcome Pressure Pain Detection Threshold (PPT) at the Superolateral Patella Site	Baseline and 6 weeks	Pain sensitisation will be measured using quantitative sensory testing (QST) to assess any changes in pain sensitisation indices from at baseline to follow-up. QST is a non-invasive method to assess pain sensitivity using standardised stimuli like mechanical pressure or sharpness. We used the QST modality pressure pain detection threshold (PPT) at anatomical position: quadricep (2cm above superolateral edge of patella). PPT measures the lowest pressure a participant perceives as painful while pressure is applied using a handheld probe (Medoc-AlgoMed, Israel) at a rate of 50 kPa/s on the most painful knee, with lower PPT threshold suggestive of increased pain sensitivity.
Changes in Pain Sensitisation Outcome Pressure Pain Detection Threshold (PPT) at the Superomedial Patella Site	Baseline and 6 weeks	Pain sensitisation will be measured using quantitative sensory testing (QST) to assess any changes in pain sensitisation indices from at baseline to follow-up. QST is a non-invasive method to assess pain sensitivity using standardised stimuli like mechanical pressure or sharpness. We used the QST modality pressure pain detection threshold (PPT) at anatomical position: quadricep (2cm above superomedial edge of patella). PPT measures the lowest pressure a participant perceives as painful while pressure is applied using a handheld probe (Medoc-AlgoMed, Israel) at a rate of 50 kPa/s on the most painful knee, with lower PPT threshold suggestive of increased pain sensitivity.
Changes in Pain Sensitisation Outcome Pressure Pain Detection Threshold (PPT) at the Medial Joint Line Site	Baseline and 6 weeks	Pain sensitisation will be measured using quantitative sensory testing (QST) to assess any changes in pain sensitisation indices from abeline to follow-up. QST is a non-invasive method to assess pain sensitivity using standardised stimuli like mechanical pressure or sharpness. We used the QST modality pressure pain detection threshold (PPT) at the anatomical position: medial joint line (3cm medially from medial edge of patella). PPT measures the lowest pressure a participant perceives as painful while pressure is applied using a handheld probe (Medoc-AlgoMed, Israel) at a rate of 50 kPa/s on the most painful knee, with lower PPT threshold suggestive of increased pain sensitivity.
Changes in Pain Sensitisation Outcome Pressure Pain Detection Threshold (PPT) at the Tibialis Anterior Muscle Site	Baseline and 6 weeks	Pain sensitisation will be measured using quantitative sensory testing (QST) to assess any changes in pain sensitisation indices from at baseline to follow-up. QST is a non-invasive method to assess pain sensitivity using standardised stimuli like mechanical pressure or sharpness. We used the QST modality pressure pain detection threshold (PPT) at anatomical position: tibialis anterior (5 cm distal and 1 cm lateral to the tibial tuberosity). PPT measures the lowest pressure a participant perceives as painful while pressure is applied using a handheld probe (Medoc-AlgoMed, Israel) at a rate of 50 kPa/s on the most painful knee, with lower PPT threshold suggestive of increased pain sensitivity.
Changes in Pain Sensitisation Outcome Pressure Pain Detection Threshold (PPT) at the Brachioradialis Muscle Site	Baseline and 6 weeks	Pain sensitisation will be measured using quantitative sensory testing (QST) to assess any changes in pain sensitisation indices from baseline to follow-up. QST is a non-invasive method to assess pain sensitivity using standardised stimuli like mechanical pressure or sharpness. We used the QST modality pressure pain detection threshold (PPT) at anatomical position: brachioradialis (5 cm medial and distal to the lateral epicondyle) on the arm opposite the painful knee. PPT measures the lowest pressure a participant perceives as painful while pressure is applied using a handheld probe (Medoc-AlgoMed, Israel) at a rate of 50 kPa/s on the arm opposite the painful knee, with lower PPT threshold suggestive of increased pain sensitivity.
Change in Short Chain Fatty Acid Butyric Acid	Baseline and 6 weeks	Change in serum levels of short-chain fatty acid (SCFA) butyric acid in response to the interventions. SCFA levels in serum will be measured using mass spectrometry.
Change in Functional Outcome 30-seconds Sit-to-stand (30CST)	Baseline and 6 weeks	Measures how many times a participant can rise from a chair to a full standing position in 30 seconds.
Change in Inflammatory Protein Interleukin-6 (IL-6) Levels	Baseline and 6 weeks	Change in Interleukin-6 (IL-6) inflammatory protein levels measured with the Olink for a subset of individuals. For Olink cytokine assay panels data is reported in either Normalized Protein eXpression units (NPX) units or absolute concentration units (pg/mL), with the lower limit of detection typically below 1 pg/mL for most assays.
Change in Tumor Necrosis Factor (TNF) Inflammatory Protein Levels	Baseline and 6 weeks	Change in Tumor Necrosis Factor (TNF) inflammatory protein levels measured with the Olink for a subset of individuals. For Olink cytokine assay panels data is reported in either Normalized Protein eXpression units (NPX) units or absolute concentration units (pg/mL), with the lower limit of detection typically below 1 pg/mL for most assays.
Change in Inflammatory Protein Interferon Gamma (IFN-γ) Levels	Baseline and 6 weeks	Change in Interferon gamma (IFN-γ) inflammatory protein levels measured with the Olink for a subset of individuals. For Olink cytokine assay panels data is reported in either Normalized Protein eXpression units (NPX) units or absolute concentration units (pg/mL), with the lower limit of detection typically below 1 pg/mL for most assays.
Changes in Gut Microbiome (Shannon Diversity Index)	Baseline and 6 weeks	The gut microbiome will be measured with shotgun metagenomic sequencing of stool samples and the Shannon Diversity Index will be calculated. The Shannon Diversity Index assesses both the richness (number of different species) and evenness (distribution of individuals among species) within the gut microbiome. A higher Shannon index indicates a more diverse microbiome, while a lower index suggests less diversity.
Change in Serum Endocannabinoid Anandamide (AEA) Levels	Baseline and 6 weeks	Serum levels of Endocannabinoid Anandamide (AEA) will be measured using mass spectrometry in samples collected at baseline and at follow-up (at the end of six weeks). This will help us ascertain the change in levels of Endocannabinoid Anandamide (AEA) in response to the intervention.
Change in Serum 2-arachidonoylglycerol (2-AG) Endocannabinoid Levels	Baseline and 6 weeks	Serum levels of 2-arachidonoylglycerol (2-AG) Endocannabinoid will be measured using mass spectrometry in samples collected at baseline and at follow-up (at the end of six weeks). This will help us ascertain the change in levels of 2-arachidonoylglycerol (2-AG) Endocannabinoid in response to the intervention.
Changes in Calcium Voltage-gated Channel Subunit alpha1 B Gene Expression Levels Using Transcriptomics on a Subset of Individuals	Baseline and 6 weeks	Transcriptomics will be measured using RNA sequencing of blood samples collected at baseline and at follow-up (at the end of six weeks). RNA was extracted from whole blood, and sequencing libraries were prepared and analysed using standard RNA-seq pipelines.
Changes in Solute Carrier Family 12 Member 5 Gene Expression Levels Using Transcriptomics on a Subset of Individuals	Baseline and 6 weeks	Transcriptomics will be measured using RNA sequencing of blood samples collected at baseline and at follow-up (at the end of six weeks). RNA was extracted from whole blood, and sequencing libraries were prepared and analysed using standard RNA-seq pipelines.
Changes in Sodium Voltage-gated Channel Alpha Subunit 11 Gene Expression Levels Using Transcriptomics on a Subset of Individuals	Baseline and 6 weeks	Transcriptomics will be measured using RNA sequencing of blood samples collected atbaseline and at follow-up (at the end of six weeks). RNA was extracted from whole blood,and sequencing libraries were prepared and analysed using standard RNA-seq pipelines.
Change in Short Chain Fatty Acid Acetic Acid	Baseline and 6 weeks	Change in serum levels of short-chain fatty acid (SCFA) acetic acid in response to theinterventions. SCFA levels in serum will be measured using mass spectrometry.

Countries

United Kingdom

Participant flow

Participants by arm

Arm	Count
Placebo Arm The participants in the placebo/control arm will be required to take 10g of maltodextrin for the same period of 6 weeks.	27
Diet Only Arm The participants in the dietary intervention arm will be required to take 20g of inulin for a period of 6 weeks.	26
Exercise Only Arm Joint Academy An app-based exercises platform (Joint Academy®) will be used as an intervention given to the treatment arm. The programme consists of a mixture of open and close chain exercises, a combination of concentric, eccentric and focusing on the global strength of legs including the muscles around the hips and knee joints as well as balance enhancement exercises. The intervention also includes educational sessions integrated into the programme covering the basics of OA, its treatment, self-managing symptoms of OA and the benefits of maintaining a healthy lifestyle. The exercise intervention focuses on core stability and performance, neuromuscular leg strengthening and balance enhancement.	40
Diet + Exercise Intervention Arm The participants in this arm will be required to take 20g of inulin for a period of 6 weeks and doing exercise at the same time.	24
Total	117

Baseline characteristics

Characteristic	Placebo Arm	Diet Only Arm	Exercise Only Arm	Diet + Exercise Intervention Arm	Total
Age, Continuous	69.59 Years STANDARD_DEVIATION 6.41	66.54 Years STANDARD_DEVIATION 11.39	67.75 Years STANDARD_DEVIATION 10.22	66.71 Years STANDARD_DEVIATION 8.44	67.69 Years STANDARD_DEVIATION 9.48
Body mass index	29.60 kg/m2 STANDARD_DEVIATION 4.65	30.15 kg/m2 STANDARD_DEVIATION 3.75	29.00 kg/m2 STANDARD_DEVIATION 7.15	29.60 kg/m2 STANDARD_DEVIATION 4.65	29.48 kg/m2 STANDARD_DEVIATION 5.32
Pain Numerical Rating Scale	3.52 units on a scale STANDARD_DEVIATION 2.77	4.06 units on a scale STANDARD_DEVIATION 2.85	4.21 units on a scale STANDARD_DEVIATION 2.88	3.92 units on a scale STANDARD_DEVIATION 1.75	3.96 units on a scale STANDARD_DEVIATION 2.67
Race and Ethnicity Not Collected	—	—	—	—	0 Participants
Sex: Female, Male Female	14 Participants	14 Participants	26 Participants	14 Participants	68 Participants
Sex: Female, Male Male	13 Participants	12 Participants	14 Participants	10 Participants	49 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	0 / 27	0 / 26	0 / 40	0 / 24
other Total, other adverse events	0 / 27	10 / 26	0 / 40	13 / 24
serious Total, serious adverse events	0 / 27	0 / 26	0 / 40	0 / 24

Outcome results

Primary

Change in Numerical Rate Score (NRS) for Pain

The Numerical Rate Score (NRS) will be used to assess the changes in the level of pain in response to the intervention between baseline and follow-up. Participants reported their pain on a scale ranging from 0 to 10, where 0 represents no pain and 10 the worst pain imaginable.