Clinical trial NCT05248386
Conditions: Osteoarthritis
Keywords: Knee, osteoarthritis pain assessment
Sponsor: Grünenthal GmbH
Start date: 2022-08-26; Completion date: 2024-11-18
Enrollment: 469 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A double-blind, randomized, placebo-controlled, parallel-group, multi-site, clinical trial to confirm the efficacy and safety of repeated injections of RTX-GRT7039 versus placebo in patients who have pain associated with osteoarthritis of the knee despite standard of care.

Detailed description:
This trial comprises a total observation period of up to 52 weeks.

Arms: arm 1: Participants will receive intra-articular injections of RTX-GRT7039 during the 52-week double-blind treatment period. arm 2: Participants will receive intra-articular injections of placebo matching to RTX-GRT7039 during the 52-week double-blind treatment period.
Interventions: intervention 1: RTX-GRT7039 intervention 2: Placebo
Intervention descriptions: intervention 1: RTX-GRT7039 intra-articular injection. intervention 2: Placebo matching RTX-GRT7039 intra-articular injection.

Protocol documents:
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1
PROTOCOL SYNOPSIS
1.1
Trial design
This is an interventional, Phase III, double-blind, randomized, placebo-controlled, parallel-group, 
multi-site, clinical trial to confirm the efficacy and safety of repeated injections of RTX-GRT7039
versus placebo in subjects who have moderate to severe pain associated with osteoarthritis of the 
knee despite receiving continued treatment with optimal standard of care (SoC) or who are unable 
to receive SoC treatment due to contraindications or intolerability. 
Approximately 450 subjects will be randomized to receive either RTX-GRT7039 or placebo in a 
1:1 ratio. In addition to continued SoC treatment, subjects will receive 1 of the following 
treatments:
•
RTX-GRT7039 400 ng intra-articular injections. 
•
Placebo to match RTX-GRT7039 intra-articular injections. 
Subjects will each receive 2 injections of investigational medicinal product (IMP) during the 
Double-blind Treatment Period (on Day 1 and at Week 26). For the second injection, subjects will 
receive the same IMP that was administered at the first injection, in a double-blind manner. 
1.1.1
Trial design chart
See Figure 1 for an illustration of the trial design.
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IA = intra-articular; IMP = investigational medicinal product; V = Visit
Figure 1:
Trial design chart
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Objective
Endpoint/Outcome
A secondary comparison of interest is the difference in mean 
change from baseline in 48-hour WOMAC pain subscale score 
at Week 52 in the index knee using an 11-point (0-10) NRS 
between RTX-GRT7039 and placebo, in subjects who initiate 
treatment, as if substantial changes in background medication or 
addition of new analgesics were not available, and as if subjects 
have received 2 injections with a 26-week interval (i.e., did not 
discontinue treatment).
Demonstrate the efficacy of 
intra-articular RTX-GRT7039 on 
function compared with placebo in 
change from baseline at Week 12, at
Week 26, and at Week 52.
Change from baseline in WOMAC physical function subscale 
score at Week 12, at Week 26, and at Week 52.
Estimand
A secondary comparison of interest is the difference in mean 
change from baseline in 48-hour WOMAC physical function
subscale score at Week 12 and at Week 26 in the index knee 
using an 11-point (0-10) NRS between RTX-GRT7039 and 
placebo, in subjects who initiate treatment, as if substantial 
changes in background medication or addition of new analgesics
were not available.
A secondary comparison of interest is the difference in mean 
change from baseline in 48-hour WOMAC physical function
subscale score at Week 52 in the index knee using an 11-point 
(0-10) NRS between RTX-GRT7039 and placebo, in subjects 
who initiate treatment, as if substantial changes in background 
medication or addition of new analgesics were not available, and 
as if subjects have received 2 injections with a 26-week interval 
(i.e., did not discontinue treatment).
To assess the safety and tolerability of 
RTX-GRT7039 intra-articular 
injection.
Incidence of treatment-emergent adverse events (TEAEs).
Incidence of TEAEs leading to discontinuation in the Treatment 
and Follow-up Period after the first and after the second 
injection, respectively.
Incidence of TEAEs representing structural changes of the knee 
joint as visualized by the imaging methods assessed by the 
investigator as clinically relevant (thus constitute an adverse 
event [AE]) and as at least possibly related to the IMP (and not 
attributable to the natural progression of the disease in an 
individual patient).
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Other data to be collected that are not directly attributed to an endpoint
To evaluate subject eligibility and to describe the trial population

Demographic and other baseline characteristics: Date of signature on the informed consent form, 
sex, age, body weight, height, body mass index (BMI), race, ethnic group.

Relevant prior/concomitant treatments: all prior and concomitant treatments (i.e., non-
pharmacologic and pharmacologic) used to treat osteoarthritis and osteoarthritis pain and reasons 
for discontinuing will be collected. Prior and concomitant medications other than for osteoarthritis
will be collected.

Thorough musculoskeletal history (incl. current and past history of osteoarthritis, joint surgeries, 
fractures, joint injuries) and physical examination (incl. evaluation of joints for swelling, redness, 
tenderness).

Imaging data (X-ray and magnetic resonance imaging [MRI]), pregnancy test, and drugs of abuse 
test.
To assess the efficacy

Patient Global Assessment (PGA) of Osteoarthritis.

Patient-specific functional scale (PSFS).

WOMAC, PGIC, SF-36, and EQ-5D-5L data at time points not related to the primary and 
secondary endpoints.
To assess the safety and tolerability of RTX-GRT7039

Vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate).

Electrocardiogram (ECG).

Safety laboratory parameters (hematology, clinical chemistry, clotting, and urinalysis dipstick 
panel).

Physical examination findings.

Assessment of procedural pain related to the IMP injection.

Imaging data (X-ray and MRI).
To assess the treatment satisfaction

Treatment Satisfaction Questionnaire for Medication (TSQM) scores.
1.3
Trial subjects – the population to be studied
Inclusion criteria are reviewed at the Screening Visit (V1) and at Baseline (i.e., V2 before IMP 
administration). Subjects will only receive IMP if documentation is available showing that they 
meet all of these inclusion criteria and none of the exclusion criteria. 
1.3.1
Inclusion criteria
1.
The subject has given written informed consent to participate.
2.
The subject is ≥18 years of age at the Screening Visit.
3.
The subject has a BMI ≤40.0 kg/m2.
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4.
The subject is willing to adhere to the restricted use of concomitant treatments (see concomitant 
treatments in Section 1.4.3).
5.
The subject has a diagnosis of osteoarthritis of the knee based on American College of 
Rheumatology criteria and functional capacity class of I to III. Pain at the index knee must be 
present for at least 6 months prior to Screening Visit.
6.
The subject has a Kellgren-Lawrence (K-L) grade of 2 to 4 in the index knee (based on X-ray 
performed during Screening Visit, assessed by central readers).
7.
There is a documented history indicating that subject has insufficient pain relief with optimal 
SoC, i.e.,
a.
non-pharmacological treatment, and
b. 1 or more courses of oral non-steroidal anti-inflammatory drugs (NSAIDs) prescribed by 
their physician and
c.
where appropriate opioids, intra-articular treatment with corticosteroids, and intra-
articular treatment with hyaluronic acid 
in combination or as monotherapies,
or subject is unable to take SoC due to contraindication or intolerability to 1 or more of the SoC 
treatments above.
Further details on the definition of documented history will be provided in the electronic case 
report form (eCRF) guidance document.
8.
The investigator does not consider that any additional benefit can reasonably be expected from 
further adjustments to the subject’s pain treatment. 
9.
The subject must have a baseline WOMAC pain subscale score 5 using the 11-point (0-10)
NRS for the index knee at Screening (assessment in e-diary at V1) and at baseline (assessment 
in e-diary at V2).
10. Women of childbearing potential must have a negative pregnancy test at the Screening Visit
and prior to each administration of IMP. They must also agree to practice, at a minimum, 
acceptable measures of birth control for at least 90 days following administration of IMP.
11. Male subjects agree to use barrier contraception (condom) during sexual intercourse with 
women of childbearing potential after each administration of IMP for 90 days. The male subject 
is willing to ensure that during this period the female sexual partner is additionally practicing 
contraception, if of childbearing potential.
1.3.2
Exclusion criteria
A single re-screening is accepted for items 4, 5, 6, and 7.
1.
The subject reports a WOMAC pain subscale score of 10 on the 11-point (0-10) NRS at 
Screening (assessment in e-diary at V1) or at baseline (assessment in e-diary at V2).
2.
The subject has a WOMAC pain subscale score of ≥4 on the 11-point (0-10) NRS in the 
non-index knee at Screening.
3.
The subject has past joint replacement surgery of the index knee.
4.
The subject had an injection of either corticosteroid or intra-articular visco-supplementation
(i.e., hyaluronic acid) into the index knee within 90 days of Screening.
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5.
The subject had an injection of platelet-rich plasma or stem cells into the index knee within 6 
months of Screening.
6.
The subject applied topical capsaicin on the index knee within 3 months of Screening.
7.
The subject has a history of significant trauma or surgery (e.g., open or arthroscopic) to the 
index knee within 12 months of Screening. 
8.
The subject has any known active infection, including suspicion of intra-articular infection, 
ulcer, or open wound anywhere on the index knee.
9.
The subject has periarticular pain from any cause other than osteoarthritis, including referred 
pain, bursitis, or tendonitis.
10. The subject has ipsilateral clinical hip osteoarthritis on the side of the index knee.
11. The subject has pre-existing osteonecrosis, subchondral insufficiency fracture, atrophic 
osteoarthritis, severe bone on bone osteoarthritis, knee pain attributable to disease other than 
osteoarthritis, or the subject has rapidly progressing osteoarthritis (RPOA) Type I or Type II.
12. The subject has significant malalignment of anatomical axis (medial angle formed by the femur 
and tibia) of the target knee (varus >10, valgus >10) by X-ray as assessed by independent 
Central Readers at Screening Visit.
13. The subject has other conditions that could affect trial endpoint assessments of the index knee, 
including, but not limited to, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, 
gout or pseudogout, inflammatory bowel disease related arthropathy, peripheral neuropathy 
(e.g., diabetic neuropathy), lupus erythematosus, significant skin conditions overlying the index 
knee, acromegaly, metabolic joint diseases, and fibromyalgia.
14. The subject has significant pain in other areas, which may confound discrimination of pain 
assessment in the index knee.
15. The subject has evidence of cognitive impairment including dementia that may interfere with 
the subject’s ability to complete patient reported outcomes (PROs).
16. The subject had systemic (except inhaled corticosteroid) immunosuppressant agent within 6 
months prior to trial medication administration.
17. The subject has any surgery scheduled during the trial period.
18. The subject has current clinically significant disease(s) or condition(s) (including clinically 
significant cardiovascular disease) that may affect efficacy or safety assessments, or any other 
reason which, in the investigator’s opinion, may preclude the subject’s participation in the full 
duration of the trial.
19. The subject has a major bleeding disorder encompassing, but not limited to coagulopathy and 
any current antithrombotic and anticoagulant events.
20. The subject has a history of severe allergic or anaphylactic reactions.
−
The subject has a history of hypersensitivity to local anesthetic (e.g., lidocaine, 
ropivacaine).
−
The subject has a history of hypersensitivity to resiniferatoxin (RTX) or any similar 
component (capsaicin, chili peppers).
21. The subject has a known infection of human immunodeficiency virus, or known current acute 
or chronic hepatitis B or C infection.
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22. The subject has unstable or poorly controlled blood pressure which, in the opinion of the 
investigator, would put the subject at risk of severe adverse blood pressure increases upon IMP 
application.
23. The subject has evidence or history of severe psychiatric illness/disorder during the 3 years 
prior to the Screening Visit that, in the investigator’s opinion, may affect efficacy or safety 
assessments or may compromise the subject’s safety during trial participation (e.g., major 
depression, major anxiety disorder, psychosis, severe personality disorders).
24. The subject has a history of alcohol or drug abuse or was actively abusing drugs (including 
alcohol, medication) during the 1 year prior to the Screening Visit as judged by the investigator.
25. The subject has past or pending litigation due to chronic pain or disability.
26. The subject is known or suspected of not being able to comply with the requirements of the trial 
protocol or the instructions of the trial site staff.
27. The subject is not able to communicate meaningfully with the trial site staff.
28. The subject is currently participating or was participating in another investigational drug trial 
within 3 months prior to the Screening Visit.
29. The subject is an employee of the investigator or trial site, with direct involvement in the 
proposed trial or other trials under the direction of that investigator or trial site or is a family 
member of the employees or the investigator.
30. The subject has contraindications to an MRI of the index knee.
31. The subject has a history of malignancy within 2 years prior to the Screening Visit, with the 
exception of basal cell carcinoma.
32. The female subject is pregnant, planning on becoming pregnant, or is currently breastfeeding.
1.4
Trial treatments
1.4.1
Investigational medicinal products
The IMPs used in this trial are given below:
•
5mL RTX-GRT7039 solution for intra-articular injection is constituted from 2 vials: 1 vial 
containing 1.6 µg/mL RTX supplied in 0.4 mL ethanolic solution and 1 vial containing 
8 mL D-α-tocopherol polyethylene glycol succinate (TPGS) buffer.
•
5 mL placebo solution for intra-articular injection is constituted from 2 vials: 1 vial 
containing 0.4 mL ethanolic solution (placebo to match RTX-GRT7039) and 1 vial 
containing 8 mL TPGS buffer.
Details will be outlined in the pharmacy manual.
A total 5 mL of IMP will be injected following ropivacaine administration (see Section 1.4.2), into 
the knee joint.
It is strongly recommended that the injection is assisted by ultrasound. Once completed, the needle 
and syringe will be removed, and an adhesive bandage applied. 
The first IMP injection will occur at the Randomization Visit (V2/Day 1) and a second injection of 
IMP will be administered at 6 months (V6/Week 26). Re-injection is not allowed if the subject did 
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not tolerate previous IMP injection as judged by the investigator or if they developed 
hypersensitivity to the IMP.
1.4.2
Other medication/treatments
Fifteen minutes prior to the intra-articular injection of IMP, a 5 mL intra-articular injection of 
ropivacaine 0.5% will be administered as a local anesthetic. Separate needles should be used for 
each, and the skin should be cleaned again prior to the administration of IMP.
Further details regarding the administration of ropivacaine are specified in a separate manual.
1.4.3
Prohibited and allowed medications or therapies
Subjects should not receive any of the following medications or therapies for the indicated times 
specified below:
•
Intra-articular injection of corticosteroid or intra-articular visco-supplementation (i.e., 
hyaluronic acid) in the index knee within 90 days before Screening and throughout the trial
•
Intra-articular injection of platelet-rich plasma or stem cells into the index knee within 6 
months of Screening and throughout the trial
•
Topical capsaicin on the index knee within 3 months of Screening and throughout the trial
•
Any surgical intervention on the index knee (including but not limited to, arthroscopic 
interventions and knee replacement surgery) throughout the trial
•
Any other investigational treatment or therapy
Subjects should continue their baseline non-pharmacological treatments and baseline analgesic and 
osteoarthritis medication(s) as long as the medications are not prohibited as outlined below, if they 
are on a stable, well-defined treatment regimen for at least 1 month before allocation to IMP and are 
anticipated to be able to maintain the treatment regimen in the opinion of the investigator.
There should be no changes (increases, decreases, or switches) from or additions to baseline 
analgesic medications (NSAIDs, opioids, other) and nonpharmacologic treatments after the 
Screening Visit. This is designed to minimize possible confounding treatment effects due to 
alterations in pain medications.
Furthermore, subjects should not schedule any medical procedures which would likely require an 
adjustment in pain medications during the trial and in particular for Weeks 10 to 12, Weeks 24 to 
26, Weeks 36 to 38, and Weeks 50 to 52, if possible. Subjects not taking opioids at baseline should 
similarly refrain from starting opioid treatment.
If for any reason deemed necessary by the investigator, a subject requires additional medication(s) 
or change of dose, the medication(s), dosage change, route of administration, start and stop dates, 
and the indication for which it was given must be recorded in the source documents and a specific 
page in the eCRF.
All vaccinations, including Coronavirus disease 2019 (COVID-19), are permitted during the trial.
1.5
Statistical analyses
All statistical methods will be detailed in a statistical analysis plan (SAP). The SAP will be 
finalized prior to database lock and unblinding.
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1.5.1
Sample size rationale
Effect size estimates were based on relevant literature and the results of available MTX-071-P03 
trial results utilizing the absolute change from baseline to Week 12 endpoint. A total number of 
382 subjects are required to achieve an overall power of at least 90% to reject the null hypothesis of 
no treatment difference in treatment group means between RTX-GRT7039 and placebo (2-sided 
t-test, type I error of α = 0.05). This is based upon an expected treatment difference of at least 1 
point on 11-point (0-10) NRS (absolute change from baseline in the WOMAC pain subscale score) 
on the primary efficacy endpoint and a standard deviation of 3 in both treatment groups.
To be able to conduct confirmatory testing for the secondary endpoints, an alpha-adjustment will 
need to be taken into consideration. The sample size is, therefore, expected to be approximately a 
total of 450 subjects (225 on placebo and 225 on RTX-GRT7039) including no more than 
90 subjects from Japan. 
Assuming a screening failure rate of about 40%, approximately 750 subjects are planned to be 
screened to randomize 450 subjects for the primary analysis (225 evaluable subjects for the 
RTX-GRT7039 treatment arm, and 225 for the placebo arm, 1:1 randomization).
1.5.2
Subject populations
Safety Analysis Set
Defined as all subjects with at least 1 IMP administration (including incomplete administrations).
Analyses on the Safety Analysis Set (SAF) will be conducted based on actual treatment received.
Full Analysis Set
Defined as all randomly assigned subjects with at least 1 IMP administration (including incomplete 
administrations).
Analyses on the Full Analysis Set (FAS) will be conducted based on the treatment as randomized 
(i.e., based on planned treatment).
1.5.3
Statistical methods and analysis
To evaluate the primary endpoint, the WOMAC pain subscale with a 48-hour recall period will be 
assessed weekly using e-diaries. The WOMAC pain subscale is comprised of 5 questions regarding 
the amount of pain experienced due to osteoarthritis in the index knee in the past 48 hours using an 
11-point (0-10) NRS. The WOMAC pain subscale score will be calculated as the mean of the 
non-missing scores from the 5 individual questions, which may not be a whole (integer) number. 
The baseline WOMAC pain subscale score is defined as the assessment made at the Randomization 
Visit (V2).
The estimand of interest for the primary efficacy analysis is the difference in mean change from 
baseline in 48-hour WOMAC pain subscale score at Week 12 in the index knee using an 11-point 
(0-10) NRS between RTX-GRT7039 and placebo, in subjects who initiate treatment, as if 
substantial changes in background medication or addition of new analgesics were not available.
The primary efficacy analysis will be performed using a mixed-effects model for repeated measures 
(MMRM). The model will include fixed effects of treatment, country/region, gender, time 
(corresponding to trial week), and treatment-by-time interaction. The baseline value will be a 
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covariate. Time will be included in the MMRM analysis to account for the correlation in repeated 
measures within-subject. An unstructured [UN] covariance matrix will initially be fitted to the 
MMRM. In the event that the analysis model does not converge, then the Toeplitz (TOEP) will be 
used as the covariance matrix. The auto-regressive (1) [AR(1)] covariance matrix will be used if 
TOEP also fails to converge. In the event that AR(1) also results in non-convergence, the compound 
symmetry covariance matrix [CS] will be used.
Individual sites will be pooled by geographic region. Geographic regions will be defined in the SAP 
and correspond to the country/region used in the stratified randomization. 
For the primary analysis the following intercurrent events (IE) will be considered:
•
A substantial change in the analgesic osteoarthritis background therapy (optimal SoC) will 
be considered as an IE. For this, a hypothetical policy estimand strategy is applied. Values 
after the occurrence of the IE will be excluded from the analyses and will be imputed by the 
baseline value.
•
Any other substantial change in analgesic medication given for any other indication will be 
considered an IE. For this, a hypothetical policy estimand strategy is applied. Values after 
the occurrence of the event will be excluded from the analyses and will be imputed by the 
last observation.  
•
For the analyses on Week 52 endpoints, not having received a second dose of treatment is 
considered an IE. For this, a hypothetical policy estimand strategy is applied. Values after 
the occurrence of the IE will be imputed by the last observation or, at the latest, the 
Week 26 value. 
Sensitivity analyses will be performed.
Subgroup analyses may be considered if appropriate and will be specified in the SAP.
1.5.4
Interim analysis
No interim analyses are planned for this trial.
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1.6
Schedule of events
Trial Period
Screening Period
Treatment and Follow-up Period
Visit 
V1
(Screening Visit)
V2a
(Randomization 
Visit)
V3
± 3 
days
V4
± 3 
days
V5
±7 
days
V6a
± 3 days
V7
± 3 
days
V8
± 3 
days
V9
±7 days
V10 
Final Visit/Early 
Termination Visit b
± 7 days
Day
-30 to -1
1
8
29
85
183
190
211
267
365
Week
1
4
12
26
27
30
38
52
Obtain informed consent 
X
Collect demographic data
X
Record general and musculoskeletal 
specific medical history c
X
Record prior medications/therapies c
X
Record concomitant 
medications/therapies 
X
X
X
X
X
X
X
X
X
X
Perform physical exam
X
X
X d
X d
X d
X
X d
X d
X d
X
Record vital signs
X
X
X e
X e
X
X
X e
X e
X
X
Perform scheduled X-rays of index 
knee
X f
X
X
Perform MRI of the index knee g
X h
ECG
X
X
X
X
Check inclusion/exclusion criteria
X
X
Train subjects on e-diaries
X
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Trial Period
Screening Period
Treatment and Follow-up Period
Visit 
V1
(Screening Visit)
V2a
(Randomization 
Visit)
V3
± 3 
days
V4
± 3 
days
V5
±7 
days
V6a
± 3 days
V7
± 3 
days
V8
± 3 
days
V9
±7 days
V10 
Final Visit/Early 
Termination Visit b
± 7 days
Day
-30 to -1
1
8
29
85
183
190
211
267
365
Week
1
4
12
26
27
30
38
52
Dispense e-diary
X
Placebo response reduction training and 
accurate pain reporting training for 
subjects 
X
X
X
X
Ask subject to record WOMAC pain 
subscale score in the non-index knee in 
their e-diary
X
Ask subject to record WOMAC 
assessments for the index knee in their 
e-diary i
X
X
X
X
X
X
X
X
X
X
Check e-diary compliance j
X
X
X
X
X
X
X
X
X
X
Dispense subject trial card
X
PGIC
X
X
X
X
PGA
X
X
X
X
X
X
X
X
X
PSFS
X
X
X
X
X
X
X
X
X
EQ-5D-5L
X
X
X
X
X
X
X
X
X
SF-36
X
X
X
X
X
TSQM
X
X
X
X
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Trial Period
Screening Period
Treatment and Follow-up Period
Visit 
V1
(Screening Visit)
V2a
(Randomization 
Visit)
V3
± 3 
days
V4
± 3 
days
V5
±7 
days
V6a
± 3 days
V7
± 3 
days
V8
± 3 
days
V9
±7 days
V10 
Final Visit/Early 
Termination Visit b
± 7 days
Day
-30 to -1
1
8
29
85
183
190
211
267
365
Week
1
4
12
26
27
30
38
52
Collect urine and perform pregnancy (if 
applicable) and drugs of abuse testing
X
X
Xk
Safety laboratory
X
X
X
X
Randomization to treatment
X
Pre-treatment with ropivacaine
intra-articular injection
X
X
Intra-articular IMP injection
X
X
Ask subjects to rate their procedural 
pain l
X
X
Record adverse events m
X
X
X
X
X
X
X
X
X
X
Collect e-diary
X
Collect subject trial card
X
a)
All other assessments are completed prior to IMP administration, assessment of procedural pain, and recording of adverse events. 
b)
Subjects who discontinue or are discontinued earlier from the trial will perform the Final Visit/Early Termination Visit as a last trial visit, if possible.
c)
At Screening, a comprehensive musculoskeletal medical history is obtained. History of insufficient pain relief, inability to tolerate or contraindication to take the specified 
SoC treatments should be collected. Any prior use of medication used to treat osteoarthritis and osteoarthritis pain and prior use for all other medications should be collected.
d)
Physical examination of only the index knee at specified visits. 
e)
Body weight and BMI are not recorded at these visits
Protocol synopsis 
(extracted from final protocol)
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ID: 
 
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Grünenthal
Confidential
Protocol KF7039-01
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f)
To be performed at V1 or between V1 and V2, only if all inclusion criteria and no exclusion criteria that can be evaluated at Screening are met.
g)
Follow up MRIs may be performed in case of index knee related adverse events or unexpected increased pain scores of severe intensity, which are persistent for at least 
2 weeks despite treatment with analgesic medication according to investigator judgment.
h)
At V1 or between V1 and V2, only if all inclusion criteria and no exclusion criteria that can be evaluated at Screening are met. Use of historical MRI 30 days before 
Screening is acceptable, if no relevant change in pain occurred since then (according to investigator and subject judgement). 
i)
In the first week after an intra-articular IMP injection (i.e., Day 1 to 7 and Week 26), subjects will assess the WOMAC pain and physical function subscales with 48-hour 
recall period every 2 days. After the first week post IMP injection, the WOMAC pain subscale score will continue to be assessed weekly in the e-diary and the complete 
WOMAC will be assessed and recorded in the subject’s e-diary at the visits specified in this SoE.
j)
Starting after V1, until V10 the e-diary will be reviewed for completeness prior to initiating any treatment-associated procedures. The subject will be re-trained if needed.
k)
Urine pregnancy test only at this visit, if applicable.
l)
Subjects will be asked to rate their procedural pain (current pain intensity on the 11-point [0-10] NRS) using the tablet computer at the site at the following time points: -0.5, 
0, 0.5, 1, 1.5, and 3 hours relative to intra-articular IMP injections, with time point 0 immediately before IMP injection.
m) Adverse events of sensory loss and decrease of motor function at the index knee/the leg of the index knee should be evaluated by additional physical examinations, X-rays, 
MRIs as deemed required by the investigator. 
BMI = body mass index; ECG = electrocardiogram; e-diary = electronic diary; EQ-5D-5L = EuroQol-5 Dimension Health Questionnaire 5 Levels; exam = examination; 
IMP = investigational medicinal product; MRI = magnetic resonance imaging; NRS=numeric rating scale; PGIC = Patient Global Impression of Change; PGA = Patient Global 
Assessment of Osteoarthritis; PSFS = Patient Specific Functional Scale; SF-36 = Short Form-36 Health Survey; SoC = standard of care; SoE = schedule of events; 
TSQM = Treatment Satisfaction Questionnaire for Medication; V = Visit; WOMAC = Western Ontario and McMaster Universities Osteoarthritis Index.
Protocol synopsis 
(extracted from final protocol)
Page 17 of 17
DMS version: 
 
ID: 
 
1.0
1423148