PPV-06 Vaccine in Inflammatory Knee Osteoarthritis

This study assesses the safety and efficacy of PPV-06 active immunotherapy versus placebo in patients who have inflammatory osteoarthritis of the knee.

PPV-06 active immunotherapy will be assessed at a dose level of 10 µg. In total, 204 patients will be randomized to receive either IMP or placebo in a ratio 1:1.

Patients will each receive 6 injections of IMP or a placebo during the Double-blind Treatment Period of 104 weeks. For each SC injection, patients will receive the same IMP or Placebo that was administered at the first injection, in a double-blind manner.

The study comprises a total of 13 scheduled on site visits and 5 scheduled phone calls, which are considered appropriate to collect trial data, monitor patients' safety, and support patients' compliance to meet trial objectives.

The overall study duration by patient will be approximately 108 weeks (up to 4 weeks for screening visit and 104 weeks of study treatment). The study comprises:

• Screening period - V1 (up to - 28 days);
• Treatment induction immune response period - V2 (D1), V3 (W4), V4;
• Maintenance immune response period - V5 (W24), V6, V7 (W44), V8, V9 (W64), V10, V11 (W84), V12 ;
• Phone calls between each scheduled visits as per protocol (PC1, PC2, PC3, PC4, PC5);
• End of Study visit or Early Termination visit - V13 (W104).

Efficacy evaluations, including pain and physical function assessments, MSK examinations, MRI with contrast, clinical laboratory tests and health related quality of life (such as WOMAC, NRS, PGA, SF-36, EQ-5D-5L, PGIC, PSQI, PSFS, WPAI questionnaires by e-PRO and e-Diary) will be performed.

Safety evaluations, including physical examinations, vital signs, ECGs, X-Ray, Ultrasound (US), MRI with contrast, and clinical laboratory tests will be performed.

Concomitant medication usage will be recorded from the time of screening until the end of the study.

Inclusion criteria

• Participant has given written informed consent to participate.
• Male or female, aged at least 40 years old.
• BMI between 22 to 35kg/m² at Screening visit.
• Diagnosis of osteoarthritis of the index knee based on American College of Rheumatology (ACR) criteria and functional capacity class of I-III, with a Kellgren-Lawrence grade [KLG] 2 or 3.
• OARSI medial Joint Space Narrowing (mJSN) Grade 1 or 2 of the index knee joint, confirmed by a semi-flexed or fixed flexion weight-bearing X-Ray performed at Screening visit, and assessed by Central Reader.
• Evidence during the Screening visit of synovitis in the index knee based on ultrasound as described in the Ultrasound Doppler manual.
• Evidence of moderate to severe Synovitis on 11-point synovitis (based on Guermazi et al. score), as assessed by Rapid OA MRI Eligibility Score (ROAMES(1)), per-formed during the Screening visit and assessed by Central Reader.
• Insufficient pain relief with standard of care (i.e. non-pharmacological treat-ments, systemic non-steroidal anti-inflammatory drugs (NSAIDs) and/or other analgesics) for symptomatic OA in the index knee within 6 months prior to the Screening vis-it.
• Pain at index knee for the majority of days (>50%) during the preceding month prior to the Screening Visit.
• At Screening Visit 1a, participant reports that their typical OA knee pain in one or both knees when not using medication is ≥ 4 out of 10.
• WOMAC pain subscale score (5 items) in the range [≥4 and ≤8], using the 11-point (0-10) NRS for the index knee at Screening and Baseline visits.
• Participant is willing to discontinue all pain medications for OA except rescue medication (pa-racetamol), to adhere to the restricted use of concomitant treatments and not use prohibited pain medications throughout the clinical trial.

Exclusion criteria

• Participant had an administration of NSAID (topical, tablets) or Cox-2 Inhibitors within 2 weeks prior to the Baseline visit.
• Injection of either corticosteroid or intra-articular (IA) Visco-supplementation (i.e., hyaluronic acid) into the index knee within 1 month of Screening.
• Injection of platelet-rich plasma (PRP) into the index knee within 6 months of Screening.
• Application of topical capsaicin on the index knee within 1 month of Screening.
• Past joint replacement surgery of the index knee.
• History of significant trauma or surgery (e.g., open or arthroscopic) to the in-dex knee within 12 months of Screening.
• Scheduled surgery except dental surgery during the clinical trial period.
• Any known active infection, including suspicion of intra-articular infection, ul-cer or open wound anywhere on the index knee.
• Periarticular pain from any cause other than osteoarthritis, including referred pain, bursitis, tendinitis, soft tissue tenderness, or subacute/acute pain from injury in the index knee.
• Known presence of pre-existing MRI-based findings warranting exclusion in accordance with the ROAMES criteria, such as rapidly progressing osteoarthritis (RPOA) Type I or Type II, osteonecrosis, subchondral insufficiency fracture, atrophic oste-oarthritis, severe bone on bone osteoarthritis, or knee pain attributable to disease other than osteoarthritis, or as assessed by X-Ray, based on Central imaging Reading at Screening Visit and before the Baseline Visit.
• Significant malalignment of anatomical axis (medial angle formed by the femur and tibia) of the index knee (varus >10°, valgus >10°) by X-Ray as assessed by Central Readers at Screening Visit.
• Other conditions that could affect trial endpoint assessments of the index knee, including, but not limited to, rheumatoid arthritis, psoriatic arthritis, ankylosing spondyli-tis, gout or pseudogout, inflammatory bowel disease related arthropathy, peripheral neuropathy, lupus erythematosus, significant skin conditions such as abscesses, acromegaly, metabolic joint diseases and fibromyalgia.
• Neuropathic pain as assessed by PainDETECT questionnaire with a score of at least 18 at Screening Visit.
• Systemic (except inhaled) immunosuppressant agent within 6 months prior to trial medication administration.
• Current clinically significant disease(s) or condition(s) (including clinically significant cardiovascular disease and/or significant pain in other areas) that may affect efficacy or safety assessments, or any other reason which, in the investigator's opinion, may preclude the patient's participation in the full duration of the trial.
• Major bleeding disorder encompassing, but not limited to coagulopathy and any current antithrombotic and anticoagulant events.
• History of severe allergic or anaphylactic reactions.
• Known infection of human immunodeficiency virus (HIV), or known current acute or chronic hepatitis B or C infection.
• Unstable or poorly controlled blood pressure which, in the opinion of the inves-tigator, would put the patient at risk of severe adverse blood pressure increases upon IMP administration.
• History of malignancy within 5 years prior to the Screening visit, with the ex-ception of basal cell carcinoma.
• History of either active TB or latent TB with inadequate course of anti-tuberculous prophylaxis.
• Contraindications to an MRI (including the gadolinium contrast with a Glo-merular Filtration Rate (GFR) below 60 mL/min) of the index knee or has a pacemaker or any other implanted electronic devices. Claustrophobic patient with impossibility to under-go an MRI.
• Evidence or history of severe psychiatric illness/disorder during 3 years prior to the Screening Visit that, in the investigator's opinion, may affect safety or efficacy assess-ments or may compromise the patient's safety during trial participation.
• Known or suspected of not being able to comply with the requirements of the trial protocol or the instructions of the trial site staff.