Papers by Stuart Ratcliffe
Pain Medicine
Objective The objective was to investigate the efficacy and safety of soticlestat as adjunctive t... more Objective The objective was to investigate the efficacy and safety of soticlestat as adjunctive therapy in participants with complex regional pain syndrome (CRPS). Design A proof-of-concept phase 2a study, comprising a 15-week randomized, double-blind, placebo-controlled, parallel-group study (part A), and an optional 14-week open-label extension (part B). Methods Twenty-four participants (median age 44.5 years [range, 18–62 years]; 70.8% female) with chronic CRPS were randomized (2:1) to receive oral soticlestat or placebo. Soticlestat dosing started at 100 mg twice daily and was titrated up to 300 mg twice daily. In part B, soticlestat dosing started at 200 mg twice daily and was titrated up or down at the investigator’s discretion. Pain intensity scores using the 11-point Numeric Pain Scale (NPS) were collected daily. The Patient-Reported Outcomes Measurement Information System (PROMIS)-29, Patients’ Global Impression of Change (PGI-C), and CRPS Severity Score (CSS) were complete...
Scandinavian Journal of Pain, 2017
Background/AimsTransient receptor potential vanilloid type 1 (TRPV1) receptor antagonists have be... more Background/AimsTransient receptor potential vanilloid type 1 (TRPV1) receptor antagonists have been evaluated in clinical studies for their analgesic effects. Mavatrep, a potent, selective, competitive TRPV1 receptor antagonist has demonstrated pharmacodynamic effects consistent with target engagement at the TRPV1 receptor in a previous single-dose clinical study. The current study was conducted to evaluate the analgesic effects of a single dose of mavatrep.MethodsIn this randomized, placebo- and active-controlled, 3-way crossover, phase 1b study, patients with painful knee osteoarthritis were treated with a single-dose of 50 mg mavatrep, 500 mg naproxen twice-daily, and placebo. Patients were randomized to 1 of 6 treatment sequences. Each treatment sequence included three treatment periods of 7 days duration with a 7 day washout between each treatment period. The primary efficacy evaluation was pain reduction measured by the 4-h postdose sum of pain intensity difference (SPID) base...
Diabetes care, Oct 29, 2016
Cannabidiol (CBD) and Δ(9)-tetrahydrocannabivarin (THCV) are nonpsychoactive phytocannabinoids af... more Cannabidiol (CBD) and Δ(9)-tetrahydrocannabivarin (THCV) are nonpsychoactive phytocannabinoids affecting lipid and glucose metabolism in animal models. This study set out to examine the effects of these compounds in patients with type 2 diabetes. In this randomized, double-blind, placebo-controlled study, 62 subjects with noninsulin-treated type 2 diabetes were randomized to five treatment arms: CBD (100 mg twice daily), THCV (5 mg twice daily), 1:1 ratio of CBD and THCV (5 mg/5 mg, twice daily), 20:1 ratio of CBD and THCV (100 mg/5 mg, twice daily), or matched placebo for 13 weeks. The primary end point was a change in HDL-cholesterol concentrations from baseline. Secondary/tertiary end points included changes in glycemic control, lipid profile, insulin sensitivity, body weight, liver triglyceride content, adipose tissue distribution, appetite, markers of inflammation, markers of vascular function, gut hormones, circulating endocannabinoids, and adipokine concentrations. Safety and...
Journal of neurology, 2015
Peripheral neuropathic pain (PNP) poses a significant clinical challenge. The long-term efficacy ... more Peripheral neuropathic pain (PNP) poses a significant clinical challenge. The long-term efficacy of delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray was investigated in this 38-week open-label extension study. In total, 380 patients with PNP associated with diabetes or allodynia entered this study from two parent randomised, controlled trials. Patients received THC/CBD spray for a further 38 weeks in addition to their current analgesic therapy. Neuropathic pain severity was the primary efficacy measure using a pain 0-10 numerical rating scale (NRS). Additional efficacy, safety and tolerability outcomes were also investigated. In total, 234 patients completed the study (62 %). The pain NRS showed a decrease in score over time in patients from a mean of 6.9 points (baseline in the parent studies) to a mean of 4.2 points (end of open-label follow-up). The proportion of patients who reported at least a clinically relevant 30 % improvement in pain continued to increa...
Multiple Sclerosis Journal, 2011
Background: Open-label studies are not ideal for providing robust evidence for long-term maintena... more Background: Open-label studies are not ideal for providing robust evidence for long-term maintenance of efficacy of medicines, especially where medicines provide symptom relief and where long-term use of a placebo may be problematic and not ethical. Objective: To evaluate the maintenance of efficacy of Sativex in subjects who have gained long-term symptomatic relief of spasticity in multiple sclerosis (MS), and to assess the impact of sudden medicine withdrawal. Methods: An enriched enrolment randomized withdrawal study design was used. Eligible subjects with ongoing benefit from Sativex for at least 12 weeks entered this 5-week placebo-controlled, parallel-group, randomized withdrawal study. Each subjects’ previous effective and tolerated dose was continued. Results: A total of 18 subjects per group were enrolled. Demographics showed a mean duration of MS of 16.4 years, spasticity 12.7 years, mean duration of Sativex use of 3.6 years (median 3.4 years) and a mean daily dose of 8.25...
The Journal of Pain, 2005
The Journal of Pain, 2005
The efficacy and tolerability of Sativex®, a highly standardised cannabisbased medicine, has been... more The efficacy and tolerability of Sativex®, a highly standardised cannabisbased medicine, has been investigated in a series of randomised, double-blind, placebo-controlled studies, in symptomatic multiple sclerosis (MS) and chronic pain patients. Study medication was added to patients’ existing therapies. Patients self titrated their medication: each 100microlitre oro-mucosal spray delivered 2.7mg delta-9-tetrahydrocannabinol (THC) and 2.5mg of cannabidiol (CBD). Patients completing the randomised studies were eligible to enter a long-term, open label, safety and tolerability study, where they discontinued their randomised therapy and re-titrated using Sativex®. Diaries of daily dosing and weekly symptom severity were completed, with clinic visits at 8-weekly intervals. As of November 2003, 261 (65%) of the 404 enrolled patients were ongoing. Withdrawals were mainly due to adverse events (n 57, 14%), withdrawal of consent (n 36, 9%) or lack of efficacy (n 24, 6%). Treatment-related adverse events were not uncommon (n 341, 84.4%), but serious, treatment-related adverse events were reported in only 11 patients (2.7%). Sustained improvement in mean Numerical Rating Scale (NRS) symptom scores were observed in patients who completed 52 weeks of extension study treatment (mean NRS score spasticity Baseline (BL, Sativex®) 5.49; BL (Placebo) 5.39, Week 52 (Sativex®) 3.29; Central neuropathic pain in MS (BL, Sativex®) 6.5, (BL, Placebo) 6.4, Week 52 (Sativex®) 2.83; Peripheral neuropathic pain (BL, Sativex®) 7.29, (BL, Placebo) 7.21, Week 52 (Sativex®) 5.07). Based on the mean number of sprays per day in 118 patients who reached 52 weeks treatment (Week 12 9.21 Week 52 7.89), there was no evidence of tolerance to Sativex®. Patients consistently reported little or no intoxication (mean intoxication Visual Analog Scale (VAS) scores (0-100) 2.26 – 4.84) for the same period. This interim analysis demonstrates that Sativex® is well tolerated and provides sustained long-term symptom relief.
European Journal of Pain, 2014
Peripheral neuropathic pain (PNP) associated with allodynia poses a significant clinical challeng... more Peripheral neuropathic pain (PNP) associated with allodynia poses a significant clinical challenge. The efficacy of Δ(9) -tetrahydrocannabinol/cannabidiol (THC/CBD) oromucosal spray, a novel cannabinoid formulation, was investigated in this 15-week randomized, double-blind, placebo-controlled parallel group study. In total, 303 patients with PNP associated with allodynia were screened; 128 were randomized to THC/CBD spray and 118 to placebo, in addition to their current analgesic therapy. The co-primary efficacy endpoints were the 30% responder rate in PNP 0-10 numerical rating scale (NRS) score and the mean change from baseline to the end of treatment in this score. Various key secondary measures of pain and functioning were also investigated. At the 30% responder level, there were statistically significant treatment differences in favour of THC/CBD spray in the full analysis (intention-to-treat) dataset [p = 0.034; 95% confidence interval (CI): 1.05-3.70]. There was also a reduction in mean PNP 0-10 NRS scores in both treatment groups that was numerically higher in the THC/CBD spray group, but which failed to reach statistical significance. Secondary measures of sleep quality 0-10 NRS score (p = 0.0072) and Subject Global Impression of Change (SGIC) (p = 0.023) also demonstrated statistically significant treatment differences in favour of THC/CBD spray treatment. These findings demonstrate that, in a meaningful proportion of otherwise treatment-resistant patients, clinically important improvements in pain, sleep quality and SGIC of the severity of their condition are obtained with THC/CBD spray. THC/CBD spray was well tolerated and no new safety concerns were identified.
European Journal of Neurology, 2007
Symptoms relating to spasticity are common in multiple sclerosis (MS) and can be difficult to tre... more Symptoms relating to spasticity are common in multiple sclerosis (MS) and can be difficult to treat. We have investigated the efficacy, safety and tolerability of a standardized oromucosal whole plant cannabis‐based medicine (CBM) containing Δ‐9 tetrahydrocannabinol (THC) and cannabidiol (CBD), upon spasticity in MS. A total of 189 subjects with definite MS and spasticity were randomized to receive daily doses of active preparation (n = 124) or placebo (n = 65) in a double blind study over 6 weeks. The primary endpoint was the change in a daily subject‐recorded Numerical Rating Scale of spasticity. Secondary endpoints included a measure of spasticity (Ashworth Score) and a subjective measure of spasm. The primary efficacy analysis on the intention to treat (ITT) population (n = 184) showed the active preparation to be significantly superior (P = 0.048). Secondary efficacy measures were all in favour of active preparation but did not achieve statistical significance. The responder an...
Clinical Drug Investigation, 1998
Objectives: To investigate how individual patients with painful osteoarthritis (OA) respond to th... more Objectives: To investigate how individual patients with painful osteoarthritis (OA) respond to the non-steroidal anti-inflammatory drug (NSAID) diclofenac and the centrally acting analgesic tramadol when individual on-demand dose titration is allowed. In addition, we studied whether the differences in the mode of action of the different analgesics were important for functional outcome in OA patients. Methods: This was performed as a double-blind, crossover, randomised study in 60 patients with OA of the hip (19 patients) or knee (41 patients) without clinical joint inflammation. Patients received either tramadol (50 to 100mg up to three times daily, on demand) for 4 weeks, followed by diclofenac (25 to 50mg up to three times daily, on demand) for 4 weeks, or vice versa. The multidimensional 'Western Ontario and McMaster Universities Osteoarthritis Index' (WOMAC) questionnaire (pain, stiffness and functional impairment) was used to assess the effect of the drugs on pain and functional capability. Results: 54 patients completed both study periods. The mean (± SD) daily dose of tramadol consumed was 164.8mg (± 54.1mg) and that of diclofenac was 86.9mg (± 21.4mg). Both treatments modestly improved median pain intensity, paralleled by an improvement in functional parameters, and there were no statistically significant differences between the groups. However, individual treatment effects varied greatly, and within individual patients there were considerable variations in analgesic effectiveness between the two treatments. Consistently, pain relief correlated linearly with functional improvement. More patients reported adverse events with tramadol than with diclofenac (20 vs 3%, p = 0.0056), but there was no difference in adverse event-related withdrawals (p = 0.69). Conclusion: OA patients' response to analgesic treatment was highly individual and the response to one drug was not predictive of that to another drug. A significant proportion of patients were not treated satisfactorily with diclofenac or tramadol alone. The results obtained from a descriptive analysis of group effects (means, medians) were inappropriate for drawing conclusions on individual treatment benefits. Improvement of functional capability apparently was a consequence of pain relief. Effective pain relief should therefore be the main therapeutic goal in patients with OA where inflammation is less prominent.
Arthritis & Rheumatism, 2006
American Journal of Alzheimer's Disease & Other Dementiasr, 2009
Obesity is now a global health hazard. It not only predisposes to an array of risk factors leadin... more Obesity is now a global health hazard. It not only predisposes to an array of risk factors leading to increased morbidity and mortality amongst adults but it also has a major negative impact on children’s health. The deleterious effects of obesity on cardiovascular system have now been well acknowledged. It causes insulin resistance that in turn leads to diabetes, hypertension and cardiovascular abnormalities. The vascular effects of obesity may have a role in the development of a rapidly growing disease of late life, Alzheimer’s disease. The precise mechanisms of the association between adiposity and impairment of cognitive performance remain to be elucidated. However, negative impact of obesity on cognitive function may be, at least in part, due to vascular defects, impaired insulin metabolism and signaling pathway or a defect in glucose transport mechanisms in brain. This review examines the available data regarding the impact of obesity on cognitive function.
Pain, 2013
We evaluated the analgesic efficacy, safety and tolerability of a novel chemokine receptor 2 (CCR... more We evaluated the analgesic efficacy, safety and tolerability of a novel chemokine receptor 2 (CCR2) antagonist, AZD2423, in posttraumatic neuralgia. This was a double-blind, randomized, parallel-group, multicentre study. One hundred thirty-three patients with posttraumatic neuralgia were equally randomized to 28days' oral administration of 20mg AZD2423, 150mg AZD2423 or placebo. The primary efficacy variable was the change of average pain score from 5days at baseline to the last 5days of treatment, measured by a numerical rating scale (NRS, 0-10). The secondary efficacy measures included NRS worst pain score, patient global impression of change, pain interference on sleep and activity, and Neuropathic Pain Symptom Inventory (NPSI). The change of the NRS average pain score was not significantly different between treatment groups (AZD2423 20mg -1.54; AZD2423 150mg -1.53; placebo -1.44). There were trends towards larger reduction of NPSI total score and NPSI subscores for paroxysmal pain and paresthesia/dysesthesia by AZD2423 150mg compared to placebo. No other secondary efficacy variables differed between treatment groups. The frequency and type of adverse events for AZD2423 were similar to placebo. Increased plasma levels of chemokine ligand 2 and reduced mean levels of monocytes (-30% by AZD2423 150mg) suggested that the administrated doses of AZD2423 had interacted with the CCR2 target. The CCR2 antagonist AZD2423 demonstrated no efficacy on NRS average pain scores and most of the secondary pain variables. The NPSI data suggested possible effects on certain sensory components of pain. There were no major safety or tolerability concerns.
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Papers by Stuart Ratcliffe