A Phase IIb, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Intra-Articular Allocetra in Participants with Primary Knee Osteoarthritis.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Enlivex Therapeutics Ltd.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05]

Trial duration

15 May 2026 → ongoing

Decision date (initial)

2026-04-13

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

To assess the efficacy of intra-articular Allocetra administration to the index knee joint in comparison to Placebo as treatment for knee osteoarthritis, as assessed by the change from baseline in Western Ontario and McMaster Universities Arthritis Index (WOMAC) Pain at 3 months and the change from baseline in WOMAC Function at 3 months.

Secondary objectives 2

1. To assess additional timepoints and parameters of efficacy of intra-articular Allocetra administration to the index knee joint in comparison to Placebo as treatment for knee osteoarthritis.
2. To assess the safety and tolerability of Allocetra when administered via intra-articular injection to the index knee joint in comparison to Placebo.

Conditions and MedDRA coding

Knee Osteoarthritis

Regulatory references

Scientific advice from competent authorities

European Medicines Agency, European Medicines Agency, Food And Drug Administration, European Medicines Agency

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Age 64 years or above, at time of screening
2. Diagnosis of primary femorotibial knee OA by: a. American College of Rheumatology (ACR) clinical and radiographic criteria, AND b. knee OA symptoms for at least 3 months prior to randomization (can be based on verbal report from the participant), with the index knee being the most symptomatic.
3. Radiographic evidence of knee OA defined as Kellgren-Lawrence (KL) grade 2 or 3 in the index knee on a weight bearing x-ray using a fixed-flexion frame, confirmed by central blinded read. X-rays conducted up to 6 months prior to screening are acceptable, provided they were performed according to the required specifications and the quality is acceptable to allow confirmation of the entry criteria when read centrally.
4. Participants who are intolerant to or have failed to adequately respond within the last 24 months to at least 2 OA therapies that include: conservative non-pharmacological therapy and simple analgesics (e.g., acetaminophen); nonsteroidal anti-inflammatory drugs (NSAIDS); avoidance of activities that cause joint pain; exercise; weight loss; physical therapy; removal of excess fluid from the knee, and intra-articular corticosteroids.
5. Index knee pain meeting ALL the below criteria: a. At the first screening visit, the investigator assesses with the patient their typical osteoarthritis knee pain when not using medication as ≥ 4 out of 10. b. WOMAC Pain (normalized 0–100) score 40 or above at the Screening visit following analgesic medication washout of at least 48 hours. If the participant is receiving a long-acting analgesic the washout will be extended to 5-half-lives of the analgesic medication(s). c. WOMAC Function (normalized 0–100) score 40 or above at the Screening and Baseline visit following analgesic medication washout of at least 48 hours. If the participant is receiving a longacting analgesic the washout will be extended to 5-half-lives of the analgesic medication(s). d. Daily OA knee pain diary average numerical rating scale (NRS) score of ≥ 4.5 and ≤ 9.0 in the index knee, with no single score of 10, for 7 days during the Screening period. The last seven measurements collected up to and including the day of the pain NRS eligibility assessment, will be used to determine eligibility and will serve as the baseline ADP-NRS with a requirement of at least 4 days of data recorded. e. Observed standard deviation of the knee pain NRS intensity score during the 7 days of the Screening assessment must not exceed 1.5.
6. Stable use of permitted concomitant therapies and willingness to abstain from prohibited medications/treatments during the trial.
7. Women who are postmenopausal (≥12 months natural amenorrhea without alternative cause) or surgically sterilized (bilateral tubal ligation, bilateral oophorectomy, or hysterectomy).
8. Male participants with partners of childbearing potential, who are not surgically sterile (vasectomy) for at least 6 months prior to randomization, must use condoms with spermicide in addition to their partner’s contraception from randomization and for 90 days after last dose.
9. Ability of the participant to understand, and willingness to provide informed consent as described in this study protocol, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. This includes: a. The willingness to agree not to use specified prohibited drugs during the study including other intra-articular treatments and adhere to the protocol restrictions for concomitant therapies. b. Ability to comply with all study requirements and procedures (at the discretion of the Investigator), including any contraindications to perform a required study assessment such as imaging assessments, availability for the duration of the study, and ability and willingness to return for follow-up visits.

Exclusion criteria 21

1. Radiographic evidence of end-stage OA (KL grade 4) or bone-on-bone articulation in the index knee.
2. Rapidly progressive OA or any joint replacement of the lower limb (partial or complete, ipsilateral, or contralateral) within 6 months of randomization, any joint replacement (partial or complete) of the index knee at any time prior to randomization, or any disorder affecting musculoskeletal pain and/or function, that is expected to alter gait and/or require surgical intervention during the study and/or interfere with the evaluation of the index knee. Such disorders include, but are not limited to, symptomatic OA of the back, hips, ankle, or foot; generalized ligamentous laxity or neuromuscular disorders affecting lower limb function; lumbar radiculopathy, peripheral neuropathy, or other conditions causing referred pain to the index knee; and any other cause leading to the participant being wheelchair or bed bound.
3. Clinically significant contralateral knee OA likely to confound efficacy assessments, including screening WOMAC Pain score 40 or above following washout of at least 48 hours.
4. Clinically significant widespread pain syndromes, as assessed by the Investigator or by Widespread Pain Index (WPI), Part 1>4, (e.g., fibromyalgia complex regional pain syndrome, pain catastrophizing, long COVID syndrome), or any condition requiring prescription pain medication to manage pain other than that of the index knee.
5. Body Mass Index (BMI) >40 kg/m² at screening.
6. Any medical issue the investigator assesses would be a contraindication to the study treatment including, but not limited to: a. Uncontrolled diabetes. b. History of uncontrolled hypertension. c. Known severe cardiovascular, cerebrovascular, thromboembolic, or respiratory diseases including uncompensated congestive heart failure, ventricular arrhythmias, acute coronary disease, myocardial infarction within 6 months prior to first treatment, unstable angina, uncontrolled hypertension, severe pulmonary disease, or uncontrolled asthma, defined as symptomatic (i.e., shortness of breath and/or wheezing) despite therapy. d. History of solid organ or hematopoietic transplantation. e. History of malignancy within 5 years (excluding adequately treated non-melanoma skin cancer or in situ carcinoma). f. Regular use of anticoagulants, known coagulopathy or other bleeding disorders, or use of other medication which, in the opinion of the investigator, places the participant at excessive risk of bleeding complications from intra-articular injection. g. Any evidence of clinically significant immunodeficiency or current therapy with any systemic immunosuppressive therapy, including oral corticosteroids (> 5 mg/day of prednisone), biologics, methotrexate, or extended-release steroid use within 4 months prior to randomization. h. Chronic use of opioids, centrally acting pain medications (e.g., pregabalin, gabapentin, duloxetine, milnacipran) and muscle relaxants (e.g., cyclobenzaprine, methocarbamol, baclofen, diazepam). i. Any evidence of clinically significant active infection (anywhere in the body) or live vaccine within one month of randomization. j. Known Human Immunodeficiency Virus (HIV) infection, or active/uncured hepatitis B or C. k. Any other uncontrolled or clinically significant systemic disease (hepatic, renal, hematologic, neurologic, endocrine, psychiatric) that would jeopardize participant safety, limit participation, or compromise interpretation of data derived from the participant.
7. Clinically significant findings on screening laboratory tests or physical examinations that are not specific to OA of the knee and may interfere with study conduct or interpretation of data or increase participant risk. These include the following laboratory abnormalities: Hb <8.5 g/dL, WBC <3.5×10⁹/L or >15×10⁹/L, platelets <100×10⁹/L, creatinine >2.0 mg/dL, bilirubin >2.0 mg/dL, AST and or ALT >3× ULN.
8. Women who are pregnant, women who are breastfeeding and women of child-bearing potential (WOCBP) as defined in Appendix G.
9. Any known psychiatric or social condition that, in the opinion of the Investigator, would make the participant unsuitable for the study (e.g., severe depression/anxiety as assessed by Patient Health Quesionnaire-9 (PHQ-9) ≥15 or by the Investigator, suicidal ideation, alcohol, drug or substance abuse, currently in prison, active worker’s compensation case, or any other reason that would make it unlikely for the participant to comply with study procedures).
10. Participants with known hypersensitivities as described below: a. Known hypersensitivity to study product components (e.g., Dimethyl Sulfoxide [DMSO]). b. Participants with a high risk of a serious allergic reaction will be excluded even if a specific hypersensitivity to any component of the study treatment or its excipients is not known. High risk of hypersensitivity includes the following: i. Participants with a history of allergic/hypersensitivity reaction that required hospitalization and/or treatment with intravenous steroids/epinephrine . ii. Participants with a known allergy to more than 3 different allergens. iii. Participants with a history of severe atopic disease (including but not limited to chronic urticaria, allergic reaction with respiratory symptoms requiring systemic steroids), or iv. in the opinion of the Investigator the participant is at high risk of developing severe allergic/hypersensitivity reactions.
11. Participation in another interventional trial or receipt of Investigational Medicinal Product (IMP) within 60 days or 5 half-lives of randomization, whichever is longer, unless pre-approved by the Sponsor.
12. Known presence of any of the following clinically relevant conditions in the index knee: a. Meniscal tear requiring surgical intervention. b. acute loose bodies. c. large/fluctuating Baker’s cyst. d. symptoms of locking, intermittent block to range of motion, or loose body sensation that could indicate meniscal displacement or an IA loose body. e. Known ligament damage or osteochondritis dissecans, or f. any index knee acute trauma within 6 months prior to randomization that would interfere with the evaluation of the index knee.
13. Prior treatment with Allocetra.
14. Prior osseous or joint infection (septic arthritis), or current infection or dermatologic condition at the intended injection site.
15. Any major surgical cartilage treatment (such as, but not limited to, autologous chondrocyte implantation [ACI], osteochondral autograft transplantation surgery [OATS]) in the index knee within 12 months of randomization, or any minor surgical cartilage treatment (such as, but not limited to, microfracture) within 6 months of randomization
16. Any ligamentous repair, malalignment correction, arthroscopy in the index knee within 6 months of randomization, interventional arthroscopy within 12 months of randomization, prior osteotomy, mosaicplasty, meniscectomy with removal of over 50% of the meniscus or arthroplasty of the index knee.
17. Knee effusion requiring aspiration of the index or contralateral knee within 3 months prior to randomization, or large index knee effusion (e.g., stroke test 3+: so much fluid that it is impossible to move any of the effusion out of the medial aspect) that is anticipated to require aspiration during the study period.
18. Intra-articular corticosteroid injection in the index knee within 3 months prior to Randomization.
19. Viscosupplement (e.g., hyaluronic acid [HA]) injection, platelet-rich plasma (PRP) injection, bone marrow aspirate or bone marrow aspiration concentrate, placental-derived tissue/cells, adipose tissue, or any other cellular or biologic product injected into the index knee within 6 months prior to randomization.
20. Known presence of any of the following joint-related conditions: a. Current or prior clinically significant inflammatory arthropathy or crystal-deposition arthropathy (e.g., rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, gout affecting any joint (calcium pyrophosphate deposition disease), pseudogout, chondrocalcinosis, hemochromatosis, villonodular synovitis, synovial chondromatosis, or other disorder other than osteoarthritis that in the opinion of the Investigator could cause inflammation of the knee). b. Major joint dysplasia or congenital abnormalities (aseptic osteonecrosis, acromegaly, Paget disease, Ehlers-Danlos syndrome, Stickler syndrome). c. Clinically significant malalignment (>10 varus/valgus in the femorotibial axis; knee flexion contracture >10) or ligamentous instability ≥ grade II in the index knee (participants with clinically well-compensated instability such as well compensated Anterior Cruciate Ligament (ACL) instability can be included). d. Any known severe systemic cartilage and/or severe bone disorder, such as hereditary diseases (Chondrodysplasia, Osteogenesis Imperfecta, etc.). e. Any known current or prior tumor of the index knee.
21. Any condition that in the Investigator’s opinion could confound study results or place the participant at undue risk.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. The change from baseline of the WOMAC Pain score at 3 months between Allocetra and Placebo.
2. The change from baseline for the WOMAC Function score at 3 months.
3. Incidence and severity of Adverse Events (AEs), treatment disruptions/ discontinuations and evaluation of safety laboratory values up to 6 months.

Secondary endpoints 6

1. The change from baseline of the WOMAC Pain score at 6 months.
2. The change from baseline of the WOMAC Function score at 6 months.
3. The change from baseline for the WOMAC Total score at 3 months.
4. The change from baseline of the WOMAC Total score at 6 months.
5. The change from baseline of the Average Daily Pain Numerical Rating Scale (ADP-NRS) at 3 months.
6. The change from baseline of the ADP-NRS at 6 months.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Enlivex Therapeutics Ltd.

Sponsor organisation

Enlivex Therapeutics Ltd.

Address

14, Einstein Street

City

Nes Ziona

Postcode

7403618

Country

Israel

Scientific contact point

Organisation

Enlivex Therapeutics Ltd.

Contact name

VP Clinical

Public contact point

Organisation

Enlivex Therapeutics Ltd.

Contact name

CEO

Third parties 6

Locations

1 EU/EEA country · 3 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 11 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications