A proof of concept randomized, double-blind, parallel group, controlled dose-finding and safety study of STR-324 in post-operative pain

STR-324 is a enkephalinase inhibitor that has shown strong analgesic activity
in animals. A Phase I study in humans demonstrated that STR-324 was
well-tolerated and had a favourable safety and tolerability profile in healthy
subjects. We now propose a study in postoperative pain to assess the analgesic
effect of STR-324, as compared to standard clinical care using morphine HCl as
postoperative analgesic.

The main objective of this dose-finding study is to evaluate the analgesic
effect of STR-324 (maximum 4 increasing doses and maximum 2-hours infusion) on
post-operative pain, measured by change of pain intensity assessed on a
Numerical Rating Scale (NRS) using an 11-point scale (0-10).

This study involves two separate steps:
The first step (single-blind standard group), involving a total of 12 patients,
aims to verify the sensitivity of the study setup in the proposed surgery to
confirm the validity of the surgery according to the pain and enrolment rate
using the established standard treatment (i.e. morphine).
After the first step, data collected on the primary endpoint will be reviewed
in order to confirm the sensitivity of this specific pain model. If the
sensitivity is not confirmed after step 1, the study will be stopped and study
design will be reviewed.
The second step (dose-finding study) is a randomized, double-blind, parallel
groups, controlled clinical trial involving a total of 106 patients divided
into two groups in which patients will be randomized between STR-324 and
morphine HCl in a ratio of 3/1:
Group 1 (n= 53 - 40 verum / 13 morphine HCl): Titration initiated with a 4-mL
bolus of the solution
Group 2 (n= 53 - 40 verum / 13 morphine HCl): Titration without initial bolus

Group 1 and 2 will be allocated randomly. Primary analysis of step 2 will be
performed as an intention to treat analysis.

see study design and relevant pages in the research protocol.

5.1.1 Step 1: Standard group
Morphine HCl will be administered by intermittent boluses:
Total dose administered and stopping criteria will be based on site practice.
5.1.2 Step 2: Test group
Depending on the randomization, the titration will be initiated with a 4-mL
(corresponding to 1 mg of STR-324) bolus of the solution (Group 1) or without
initial bolus (Group 2). The STR-324 and morphine HCl titration protocol is
based on continuous infusion with increasing
rates will be tested (5, 10, 20 and 40 mL/h):
Dose 1: 5 mL/h infusion rate (corresponding to 1.3 mg/h of STR-324 or morphine
HCl)
Dose 2: 10 mL/h infusion rate (corresponding to 2.6 mg/h of STR-324 or morphine
HCl)
Dose 3: 20 mL/h infusion rate (corresponding to 5.1 mg/h of STR-324 or morphine
HCl)
Dose 4: 40 mL/h infusion rate (corresponding to 10.2 mg/h of STR-324 or
morphine HCl)
Study drug administration description:
Titration: continuous infusion with increasing infusion rates every 5 minutes
until after titration, if pain score is still > 3 at highest dose level: the
study drug will be interrupted and the patient is switched to standard pain
management according to the site practice this dose level up to 2 hours.
If during the 2h period score re-increases over 3:
The maximum dose level of study product was not achieved (i.e. maximum infusion
rate):
Re-escalation of infusion rate every 5 min based on pain score up to the
highest dose level
Pain score > 3 at highest dose level after re-escalation: Switch to standard
pain management.
After 2 hours, all patients will be switched to standard pain management.
The exposure to study drug will be lasting from 20 min (maximal titration time
up to the highest dose) to a maximum of 2 hours.
Of note, aggravation of the sedation score up to S3 as well as agitation or
delirium episodes occurring during or after the study drug administration shall
be reported as adverse events.

This study aims to evaluate the analgesic effect and the safety of STR-324
administered as an infusion, with or without initial bolus, to patients
suffering from post-operative pain. The protocol is based on an initial dose of
1.3 mg/h infusion rate with periodic re-evaluation of the pain and, in case of
no response, the possibility of gradually increasing the dose up to the maximum
dose (10.2 mg/h).

During this phase IIa clinical trial, the maximal dose is set at 10.2 mg/h and
such maximal dose will be achieved after several titration steps. However, a
specific attention will be brought to any adverse event, and particularly to
the potential effects that could result from the pharmacologic properties of
STR-324.

The potential benefit from STR-324 administration consists of analgesia without
opioid-like side effects.

Treatment of non-responder patients at the highest dose will be discontinued
and replaced with the site standard pain management treatment. Patients
responding to the study drug will be followed for a period of two hours and
then systematically switched to the site standard pain management treatment.

The exposure to study product will last at least 20 minutes (time required to
reach the maximum infusion rate) and at most 2 hours. The duration of morphine
treatment will follow the same schedule and therefore cannot exceed 2 hours.

The proposed pain model is similar with the usual post-operative pain
management practice; however, the authorized concomitant analgesic medications
differ from the usual practice. In this context, in order to confirm the
sensitivity of the pain model used in the trial prior to conducting the study,
a standard group of patients treated with morphine is planned to be enrolled in
the proposed surgery (Aubrun et al., 2003; Sitbon et al., 2016).

Sponsor considers that the previous data collected in animals and humans, the
rationale and the design of this study are in favour of a positive benefit/risk
balance for the patients who will participate.