Category Archives: Clinical Studies

Invited Speech at NIH Pain Workshop Washington DC Nov 15th 2018 (Video Cast)

Dr. med. Schaffler was a invited Speaker at NIH Workshop on the topic
Discovery and Validation of Biomarkers to Develop Non-Addictive Therapeutics for Pain

Session:
Emerging Tools and Approaches in Biomarker Discovery and Development

Title:
Predictive validity of human Laser-EPs in extended phase-I IND analgesic research

Look Video Cast of NIH Pain Workshop in Washington DC:
Link: https://videocast.nih.gov/summary.asp?Live=28514&bhcp=1

Start looking from 1:25h for presentation Day 2 Nov 15th 2018
(about 20min, Dr.K.Schaffler HPR – Discussion later)

A Phase I, randomized, double-blind, laser evoked potential study to evaluate the analgesic/anti-hyperalgesic effect of ASP9226, a state-dependent N-type voltage-gated calcium channel inhibitor, in healthy male subjects

K. Schaffler, A. Fakhoury, W. He, P. Passier, K. Tracy, J. Paul

in print, Pain Medicine, DOI: 10.1093/pm/pnx338

Excerpt:

Abstract

Objective

Evaluate the analgesic/antihyperalgesic effects of ASP9226, a state-dependent N-type voltage-gated calcium channel inhibitor, in healthy male subjects.

Design

Randomized, double-blind, double-dummy, placebo- and active comparator–controlled crossover study.

Setting

HPR Dr. Schaffler GmbH, Munich, Germany.

Subject

Healthy male subjects aged 18–55 years.

Methods

Twenty-four eligible subjects were randomly assigned to one of four treatment sequences and received single doses of ASP9226 (30 mg or 50 mg), pregabalin (150 mg), or placebo during four treatment periods. Laser-evoked potentials (LEP) and postlaser pain visual analog scales (VAS) on capsaicin-treated skin were assessed during main assessment days (the first day of each study period). Primary and secondary end points were the differences in LEP N2-P2 peak-to-peak (PtP) amplitudes and VAS score, respectively, in all subjects.

Results

Overall, treatment with pregabalin resulted in a significantly lower LEP N2-P2 PtP amplitude vs placebo (–3.30 μV, P < 0.0001). There were no clinically relevant differences in N2-P2 PtP amplitudes between placebo and either ASP9226 dose (–0.31 μV and –0.27 μV). Furthermore, subjects reported significantly lower VAS pain scores with pregabalin vs placebo (–9.90%, P < 0.0001) in contrast to ASP9226 30 mg (–2.1%) and ASP9226 50 mg (1.2%) vs placebo. Subgroup analysis of LEP and VAS pain in participants with positive prestudy capsaicin response (n = 13) were in keeping with results in all subjects.

Conclusions

ASP9226 was well tolerated; however, there was no improvement in LEP and VAS pain scores with ASP9226 at either dose vs placebo.

Investigation of the predictive validity of laser- EPs in normal, UVB-inflamed and capsaicin-irritated skin with four analgesic compounds in healthy volunteers

BCJP_Pred.Validity_LEP_03.2017_T1

Klaus Schaffler, Laurent B. Nicolas, Andreas Borta, Tobias Brand, Peter Reitmeir, Robert Roebling and Joachim Scholpp in Br J Clin Pharmacol (Jan 2017) DOI:10.1111/bcp.13247

Abstract:

AIMS
The aim of the present study was to assess the predictivity of laser-(radiant-heat)-evoked potentials (LEPs) from the vertex electroencephalogram, using an algesimetric procedure, testing the anti-nociceptive/anti-hyperalgesic effects of single oral doses of four marketed analgesics (of different compound classes) vs. placebo, in healthy volunteers with three skin types.
METHODS
This was a randomized, placebo-controlled, single-blind, five-way-crossover trial. Twenty-five healthy male/female Caucasians were included (receiving celecoxib 200 mg, pregabalin 150 mg, duloxetine 60 mg, lacosamide 100 mg or placebo) in a Williams design, with CO2 laser-induced painful stimuli to normal, ultraviolet (UV) B-inflamed and capsaicin-irritated skin. LEPs and visual analogue scale ratings were taken at baseline and hourly for 6 h postdose from all three skin types.
RESULTS
In normal skin, the averaged postdose LEP peak-to-peak-(PtP)-amplitudes were reduced by pregabalin (2.68 μV; 95% confidence interval (CI) 4.16, 1.19) and duloxetine (1.73 μV; 95% CI 3.21, 0.26) but not by lacosamide and celecoxib vs. placebo.
On UVB-irradiated skin, reflecting inflammatory pain, celecoxib induced a pronounced reduction in LEP PtP amplitudes vs. placebo (6.2 μV; 95% CI 7.88, 4.51), with a smaller reduction by duloxetine (4.54 μV; 95% CI 6.21, 2.87) and pregabalin (3.72 μV; 95% CI 5.40, 2.04), whereas lacosamide was inactive.
LEP PtP amplitudes on capsaicin-irritated skin, reflecting peripheral/spinal sensitization, as in neuropathic pain, were reduced by pregabalin (3.78 μV; 95% CI 5.31, 2.25) and duloxetine (2.32 μV; 95% CI 3.82, 0.82) but not by celecoxib or lacosamide vs. placebo, which was in agreement with known clinical profiles. Overall, PtP amplitude reductions were in agreement with subjective ratings.
CONCLUSIONS
LEP algesimetry is sensitive to analgesics with different modes of action and may enable the effects of novel analgesics to be assessed during early clinical development.

 

HPR Poster Presentation at the 15th World Congress on Pain in Buenos Aires 2014

First Clinical Translation of the Anti-Nociceptive/Anti-Hyperalgesic Efficacy of a T-Type Calcium Channel Modulator (Z944) – Using Laser Evoked Potentials and VAS in UV-B and Capsaicin Irritated Skin in Healthy Humans

K. D. Schaffler Germany,Head, HPR-Human Pharmacodynamic Res., Munich; M. S. Lee, Res. & Translational Med., Zalicus Pharmaceuticals Ltd., Cambridge, MA, USA; M. Versavel, Zalicus Pharmaceuticals

The IASP congress took place October 6 – 11, 2014 – in Buenos Aires.

Please download HPR poster here.

HPR Dr. Schaffler GmbH in cooperation with Zalicus announces positive results of Z944 Phase 1B Clinical Study in Pain

Positive results of Z944 Phase 1B Clinical Study in Pain

Efficacy Signals in Inflammatory and Neuropathic Pain Observed

Second U.S. Patent Issues for Z944 Providing Exclusivity to 2029

Munich, Germany – June 17th, 2014 – HPR Dr. Schaffler GmbH, a contract research organization, which conducts Phase 1 clinical trials in the field of CNS pain research, announced positive results of a Phase 1b clinical study for its customer Zalicus (Z944). Research object is a novel oral T-type calcium channel modulator in development for the treatment of pain. The Phase 1b study is an experimental clinical model utilizing Laser-Evoked-Potentials (LEP) to provide both objective and subjective assessments of the activity of Z944 in induced pain states. Based on these results, Zalicus is planning to advance a modified-release formulation of Z944 into Phase 2 clinical development in an appropriate pain indication in 2014. In addition, a second United States patent for Z944 (U.S. Patent number 8,569,344) covering methods of treating pain was issued on October 29, 2013, providing additional patent protection for Z944 in the United States until at least 2029.

“This is the first T-type calcium channel modulator to demonstrate clinical translation in pain, and these results are indicative of Z944’s potential activity in modulating pain signaling. We look forward to further evaluating a modified release formulation of Z944 in a relevant clinical pain syndrome in 2014,” commented Mark H.N. Corrigan, MD, President and CEO of Zalicus.

This exploratory, double-blind placebo-controlled, randomized cross-over, Phase 1b clinical study enrolled 16 healthy volunteers and was conducted in a single center in Germany.
The primary objective of the study was to compare the analgesic/anti-hyperalgesic properties of three different single doses of Z944 in a model of inflammatory pain and in a model of chronic neuropathic pain as compared with placebo.
Highlights of the results of the Z944 Phase 1b LEP study results include:
Statistically significant and meaningful reductions at each of the three doses compared to placebo of overall peak-to-peak (PtP) amplitude of LEPs in models of both inflammatory (p≤0.0002) and neuropathic (p<0.05) pain. Consistent trends in reduction of subjective pain scores compared to placebo using a visual analog scale in both pain models. Meaningful trends in effects based on dose and concentration, providing important insights into the potential therapeutic window and effective plasma concentrations of Z944. Z944 was generally well tolerated with dose dependent CNS side effects and no serious adverse events.
In this study, hypersensitivity to laser thermal stimulation was induced by UV light exposure as a model of inflammatory pain and by topical capsaicin as a model of neuropathic pain. Electrical voltage fluctuations evoked by laser thermal stimulation were quantified with vertex-Electroencephalography(EEG) in addition to a subject-reported pain score. Many currently approved and emerging pain drugs have been evaluated using the LEP model, providing the ability to benchmark the efficacy of Z944 against other therapies.

About Z944 and T-type Calcium Channels

Z944 is a novel, oral, state-dependent, selective T-type calcium channel modulator that has demonstrated efficacy in multiple preclinical inflammatory pain models and in a Phase 1b experimental model of pain. T-type calcium channels have been recognized as key targets for therapeutic intervention in a broad range of cell functions and have been implicated in pain signaling. Zalicus is planning to advance a modified release formulation of Z944 through further clinical development.

Please download press release for clinical study on Z944.

An oral TRPV1 antagonist attenuates laser radiant-heat-evoked potentials and pain ratings from UV(B)-inflamed and normal skin

Br J Clin Pharmacol. 75:2 / 404–414 2012 Jul 10.2012
DOI: 10.1111/j.1365-2125.2012.04377.x.


Abstract

AIMS: Laser (radiant-heat) evoked potentials (LEPs) from vertex-EEG Peak-to-Peak (PtP) amplitude were used to determine acute antinociceptive/ antihyperalgesic efficacy of ABT-102, a novel TRPV1 antagonist efficacious in preclinical pain models, compared to active controls and placebo in normal and UV(B)-inflamed skin of healthy humans.
METHODS: This was a randomized, placebo- and active-controlled, double-blind, intra-individual-crossover trial. Twenty-four healthy subjects received six sequences of single doses of ABT-102 (0.5, 2, 6 mg), etoricoxib 90 mg, tramadol 100 mg, and placebo. Painful stimuli were induced by CO(2)-laser on normal and UV(B)-inflamed skin. LEPs and visual analog scale (VAS-Pain) ratings were taken at baseline and hourly up to 8 hours post-dose from both skin types.
RESULTS: Compared to placebo, significant mean decreases in the primary variable of LEP PtP-amplitude from UV(B)-inflamed skin were observed with ABT-102 6 mg (P < 0.001), ABT-102 2 mg (P = 0.002), tramadol 100 mg (P < 0.001), and etoricoxib 90 mg (P = 0.001) over the 8-hour period; ABT-102 0.5 mg was similar to placebo. ABT-102 6 mg was superior to active controls over the 8-hour period (P < 0.05) whereas ABT-102 2 mg was comparable. Improvements in VAS scores compared to placebo were observed with ABT-102 6 mg (P < 0.001) and ABT-102 2 mg (P = 0.002). ABT-102 average plasma concentrations were 1.3, 4.4, and 9.4 ng/mL for the 0.5, 2, and 6 mg doses, respectively. There were no clinically significant safety findings.
CONCLUSIONS: TRPV-1 antagonism appears promising in the management of clinical pain, but requires further investigation.

Link to full paper here.

Dose-response relationship after single oral dose administrations of morphine and oxycodone using laser-evoked potentials on UVB- and capsaicin-irritated skin in healthy male subjects

Eef Hoeben, Johan W. Smit, David Upmalis, Sarah Rusch, Klaus Schaffler, Peter Reitmeir, Bernhard Mangold    http://dx.doi.org/10.1016/j.pain.2012.04.018

in PAIN 153 (2012) 1648–1656 (full paper here:)

Abstract: The aim of the study was to evaluate the analgesic/antihyperalgesic efficacy and to establish the dose-response relationship of morphine immediate release (IR) and oxycodone IR in a human experimental algesimetric model. Calculated effect ratios for peak-to-peak (PtP) amplitudes of laser-evoked potentials (LEPs) and visual analog scales (VAS) postlaser pain on UVB-irradiated skin (main target variables) were 1.68 and 1.18 respectively for oxycodone 10 mg/morphine 20 mg, 3.00 and 1.63 respectively for oxycodone 15 mg/morphine 30 mg, and 1.12 and 1.25 respectively for oxycodone 20 mg/morphine 40 mg. The effect on the laser-PtP amplitude of morphine at the highest dose (40 mg) and of oxycodone at all doses (10, 15, 20 mg) was considered to be clinically relevant based on a difference from placebo of >2.5 micV.
For both compounds, a statistically significant linear trend was observed between dose groups in at least 1 of the 2 main target variables (adjusted P value for both end points <.001 at all doses). Hyperalgesia developed over time vs baseline due to acute exposure to UVB irradiation and to topical/occlusive 1% capsaicin solution. For both compounds, the principal onset of analgesic/antihyperalgesic drug effects was around 0.5 hours with an average peak at about 1 to 2 hours and the effect lasting for more than 3 hours (morphine 20 and 30 mg) or 6 hours (morphine 40 mg and oxycodone all doses).
In conclusion, the study demonstrated a solid outcome of a mixed objective/subjective human experimental algesimetric model to approach dose-response relationships and analgesic/anti-hyperalgesic effects of 2 opioids.