A multi-country, randomized, double-blind, placebo-controlled study investigating the efficacy and safety of STA363 at two concentrations (60 mg/mL and 120 mg/mL) compared to placebo in patients with chronic discogenic low back pain

Chronic low back pain (cLBP) is a major health problem and a significant burden
to patients as well as society [1]. It is one of the leading causes of work
absenteeism and health care-related costs [1]. Despite its high prevalence,
there are diagnostic challenges, and, in many patients, the proximate cause of
the pain cannot be accurately determined. Nevertheless, it has been estimated
that more than a third of the cases of chronic low back pain has a discogenic
etiology [2]. Diagnosis is made by clinical presentation and imaging [3],
predominantly magnetic resonance imaging (MRI) tomography. Provocative
discography has been abandoned by many physicians since the usefulness of
discography in predicting the outcome of lumbar fusion surgery is low [4].
Spinal fusion surgery is one therapeutic option for patients suffering from
cLBP not responding sufficiently well to physio- and pharmacotherapy. The
procedure dates back to 1889 but it is in the past 20 years that there has been
a great escalation internationally in its use. However, as for all types of
surgery, there is a risk for complications and a considerable rehabilitation
period. There are several indications for spinal fusion surgery with
degenerative disc disease representing 7% of the cases in Sweden in 2014
according to the Swedish Spine Registry [5]. The efficacy of spinal fusion
surgery in degenerative disc disease is limited and approximately one third of
the patients report no improvement or even worsening of pain one year after the
intervention [5]. In 5-year follow-up surveys, similar results have been
obtained [5]. Martin et al. examined the USA National Inpatient Sample database
from 2004 to 2015 and found that the volume of elective lumbar fusion increased
by 62.3% (or 32.1% per 100,000 US adults), from 122,679 cases (60.4 per
100,000) in 2004 to 199,140 (79.8 per 100,000) in 2015. While increases were
observed for all diagnoses during the examined 10-year period, those for disc
herniation and disc degeneration declined during the most recent years of the
study (2013-2015), perhaps as a result of publications challenging conventional
thought for these indications, increased scrutiny from payers, and/or improved
documentation reflecting more accurate coding [6]. Harris et al. aimed to
summarize
systematic reviews on the effectiveness of lumbar spine fusion for most
diagnoses. They found no high quality systematic reviews and the risk of bias
of the randomized controlled trials in the reviews was generally high. The
available evidence did not support a benefit from spine fusion compared to
nonoperative alternatives for back pain associated with degeneration [7]. There
is thus a clear medical need for new treatment options for cLBP caused by
degenerative disc disease. Alterations in disc morphology can be seen as early
as in adolescence [8] and are often referred to as *degenerative* changes.
Since age-related changes in disc structure eventually develop in all
individuals, the concept of disc degeneration has been challenged, as the term
implies a pathological process rather than normal aging. However, in some
individuals diagnosed with degenerative disc disease, there is a formation of
tears and fissures of annulus fibrosus, the outer shell of the disc. These
allow inflammatory molecules known to be produced in the nucleus pulposus (NP)
(the gelatinous nucleus of the disc) of the degenerating disc to penetrate into
and even leak outside the annulus fibrosus. The discovery that disc
degeneration causes tears in the annulus fibrosus has been described by
Saifuddin et al. [9], and
MacMillan et al. [10] showed that these fissures can serve as diffusion routes
from the NP to extradiscal sites. This has been further evaluated in a rat
model in which it was demonstrated that diffusion of NP fluid from an
intervertebral disc (IVD) causes pain, whereas a superficial scratch on the
surface of the disc with no diffusion, does not [11]. Replacement of the NP
with connective tissue is a part of natural aging. Since the NP is highly
hydrated, fibrosis or at least desiccation can be seen on T2-weighted MRI as a
darkening of the center of the disc [12]. This process frequently follows a
course in which discogenic cLBP declines over time [13] which may be a
consequence of disappearance of NP and a loss of its capacity to generate
proinflammatory molecules. Cells of the NP rely on glycolysis for energy
metabolism and therefore, the levels of S-lactic acid in the disc are high
[14]. Age-related disc fibrosis may result from many different mechanisms, but
it is possible that lactic acid is one mediator. The therapeutic principle
developed by Stayble Therapeutics mimics the process of age-related disc
fibrosis. A single injection of lactic acid into an IVD has been shown to
produce a rapid (<4 weeks) and pronounced transformation of NP into connective
tissue in pigs. There may be a double therapeutic benefit from this
intervention:
1. Generation and diffusion of proinflammatory and pain-producing molecules
from the NP is
prevented.
2. Sclerotization of the disc limits motion and stabilizes the affected spinal
segment.
Stayble Therapeutics is developing STA363 ((S)-lactic acid for treatment of
cLBP of discogenic origin. The final formulation is prepared by an aseptical
reconstitution of STA363 ((S)-lactic acid 150 or 300 mg/mL (6.7 mL), with
radiocontrast formulation iohexol (Omnipaque®) 300 mg I/mL (10 mL) and should
only be used for injection into intervertebral discs (IVDs). Iohexol is used to
confirm correct intradiscal injection using x-ray imaging. The final
concentration of (S)-lactic acid is 60 or 120 mg/mL. The concentration of
iohexol is kept constant at 388 mg/mL, corresponding to 180 mg I/mL, for both
doses of (S)-lactic acid. STA363 ((S)-lactic acid acts by transforming the NP
of the IVD into connective tissue. This will prevent diffusion of
pain-producing and proinflammatory molecules, produced by the degenerating NP,
to spinal nerves. The mechanical properties of the IVD will also change so that
the motion segment becomes less flexible and consequently partly mimics the
effects of a spinal fusion. The formulation has been used for the first time in
a phase Ib study in cLBP patients.

The primary objective is to investigate the efficacy of a single intradiscal
injection of STA363 into one or two IVDs as compared to placebo by the
following primary efficacy endpoint:
* Change from baseline at Month 6 in mean pain intensity measured on a 0-10
Numerical rating scale (NRS) for 7 consecutive days

The secondary objectives are to investigate the efficacy of a single
intradiscal injection of STA363 into one or two IVDs as compared to placebo by
the following secondary efficacy endpoints:
* Change from baseline at Month 1, Month 3 and Month 12 in mean pain intensity
measured on the NRS for 7 consecutive days
* Changes from baseline at Month 1, Month 3, Month 6 and Month 12 using the
following questionnaires:
o Oswestry Disability Index (ODI)
o EQ-5D-5L
* Quantitative changes in nucleus pulposus (NP) water content (reflecting
transformation of NP into connective tissue) at Month 6 and Month 12
(T2-weighted magnetic resonance imaging [MRI] and quantification of T2)

To investigate the safety of intradiscal injection of STA363 compared to
placebo by the following safetyendpoints:
* Incidence and nature of adverse events
* Changes in physical examination findings
* Changes in vital signs (blood pressure and heart rate)
* Changes in 12-lead electrocardiogram (ECG)
* Changes in laboratory tests (hematology, clinical chemistry)
* Pain intensity at the injection site during and 15 minutes after injection
(NRS)
* Changes in IVD height (T2-weighted MRI)
* Other changes in IVD morphology (e.g. frequency of asymptomatic/symptomatic
disc protrusions, Modic changes, high-intensity zone [HIZ] as well as other
radiology findings) (T2-weighted MRI)

Exploratory objectives are to investigate the efficacy of a single intradiscal
injection of STA363 into one or two IVDs compared to placebo by the following
exploratory efficacy endpoints:
* Percentage of patients achieving >=30% reduction in mean NRS pain intensity
score from baseline to Month 6
* Percentage of patients achieving >=50% reduction in mean NRS pain intensity
score from baseline to Month 6
* Percentage of patients achieving >=30% improvement in ODI score
* Percentage of patients with success outcome defined as >=50% improvement in
NRS accompanied by a >=30% improvement in ODI
* Consumption of analgesics
* Return to work
* Time to spinal fusion surgery
* Patient Global Impression of Change (PGIC) at Month 1, Month 3, Month 6,
Month 12 measured by a 7-point Likert Scale

This is a phase IIb, prospective, multi-country, multicenter, randomized,
double-blind, placebocontrolled, parallel group study to investigate the
efficacy, safety and transformation of NP following single intradiscal
injection of STA363 (lactic acid) into one or two IVDs compared to placebo for
the treatment of discogenic low back pain. This study will be conducted in
Russia, Spain and the Netherlands. The primary objective is to demonstrate
superiority of STA363 over placebo in reducing low back pain as measured by the
NRS. A total of 168 patients will be screened in the study with the aim to
recruit 126 patients to be randomly allocated to one of the three treatment
groups:
Group 1 - 42 patients will receive STA363 containing 90 mg (60 mg/mL) lactic
acid
Group 2 - 42 patients will receive STA363 containing 180 mg (120 mg/mL) lactic
acid
Group 3 - 42 patients will receive placebo
The investigational medical product (IMP) will be injected into the center of
up to two IVDs. Patients with two discs appropriate for treatment will be
treated at both affected levels by two separate injections. Each patient will
have 5 visits to study site and 1 telephone call. The patient*s total time in
the study will be approximately 61 weeks (~15 months) including an 8-week
screening period.

Group 1 - 42 patients will receive STA363 containing 90 mg (60 mg/mL) lactic
acid
Group 2 - 42 patients will receive STA363 containing 180 mg (120 mg/mL) lactic
acid
Group 3 - 42 patients will receive placebo

Additional burden for the patient are the 5 additional visits to the hospital
which are required for the clinical trial. Also the time of such a visit is
higher than usual due to the additional interventions/assessments done during
these visits.
Total extra burden consists of:
- questionnaires (2 per visit)
- patient diary (7 days at time of visits)
- ECG (3 times)
- MRI (3 times)
- blood draws (2 times)
- physical exam (5 times)