Aims of the study
- This study assesses the safety of hUC-O. Safety is determined through adverse event assessment, laboratory tests, a vital sign assessment, a physical examination, and an electrocardiogram (ECG) test.
- This study assesses the clinical outcomes of hUC-O. Subjective preoperative and postoperative patient reports, specifically, pain visual analog scale (VAS)[18], Harris Hip scores (HHS)[19], and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)[20], are compared to assess the clinical outcomes.
- This study assesses the radiological results after hUC-O based cell therapy using simple radiography and magnetic resonance imaging (MRI). The preoperative and postoperative necrotic lesion size, the Association Research Circulation Osseous (ARCO) stage [21], and Japanese Investigation Committee (JIC) [22] stage are compared.
Study Design
The present study is an investigator-sponsored, prospective, single-institution, open-label, phase 1 clinical trial and has been approved by the institutional review board (IRB) of Kyungpook National University Hospital (IRB No. KNUH 2021-07-015) and Korea Food and Drug Administration (No. 10052). The trial was registered at the Korean Clinical Trials Register (KCT0006627) on September 30, 2021.
Study population
Inclusion criteria: Participants must fulfill all of the following conditions to qualify for study enrollment:
1) Males or females between 19 and 60 years old
2) Radiographically diagnosed with osteonecrosis on at least one side of the femoral head.
3) Have ARCO stage 1 or 2.
4) Symptom improvement or relief following 3 months of conservative treatment are deemed improbable by a researcher.
5) Have voluntarily consented to participate in this clinical trial.
Exclusion criteria: Participants who fulfill at least one of the following conditions must be excluded:
1) ONFH is deemed as rapidly progressing by a researcher.
2) Have shown clinically significant abnormal values in a screening test (Aspartate aminotransferase [AST] or alanine transaminase [ALT] levels over 2.5-fold the upper normal limit [UNL] specified by the research facility).
3) Malignant bone tumor or bone metastasis in the femoral head or proximal femur.
4) Previous history of malignant tumors (but can be included if there was no relapse within 5 years after completing a treatment).
5) Diagnosed with inflammatory arthritis of the operated joint.
6) Diagnosed with acetabular dysplasia with a lateral center-edge angle <20°.
7) Post-traumatic ONFH.
8) Systemic or local inflammatory response requiring systemic antibiotic treatment.
9) Diagnosed with human immunodeficiency virus (HIV), hepatitis B or hepatitis C infection
10) Requires continuous, systemic, and high-dose corticosteroid therapy (prednisone administration at 7.5 mg/day) or administration of immunosuppressants within 6 months after CD.
11) Stem cell therapy for ONFH before screening.
12) Heavy alcohol consumption within 6 months of screening (males ≥ 13 standard drink [10g of pure alcohol]/week, females ≥ 7 standard drink/week)
13) Have undergone CD or other treatments or procedures that can affect the femoral head at the site of the operation.
14) Body mass index (BMI) ≥ 40 kg/m2 at the time of a screening visit.
15) Females with a possibility of pregnancy and do not agree to use medically approved contraceptive methods (e.g., hormonal contraceptives, intrauterine device [IUD], intrauterine system [IUS], tubal ligation, double-barrier contraception [e.g., combined use of male and female condoms, cervical cap, contraceptive diaphragm, and contraceptive sponge], and single-barrier contraception using spermicides) during the study period.
16) Pregnant or breastfeeding.
17) Received an investigational new drug (IVD) from another clinical trial within 4 months before participating in this clinical trial.
18) Are deemed inadequate for participation in this study by a researcher.
Of the patients who consent to participate in this clinical trial, those who satisfy the inclusion and exclusion criteria will be assigned to a low-dose (n = 3), middle-dose (n = 3), and high-dose group (n = 3) in the order of their arrival at the facility without random allocation and followed up for 12 weeks. Nine patients will be assigned if no dose limiting toxicity (DLT) develops up to the highest dose. Up to 18 patients can be enrolled, depending on the development of DLT.
Procedure
CD restores normal blood circulation within the femoral head by drilling a tunnel at the site of necrosis [4]. It reduces the increased intramedullary pressure and pain by promoting revascularization within the necrotic site [7]. In this clinical trial, a competent researcher or a designated physician will perform CD and administer hUC-O through the following steps.
1) Check the size and location of the lesion before the procedure, and place the patient on the operating table.
2) Make an incision on the lateral femoral region after anesthetizing the patient. Insert a guide pin for core decompression under the fluoroscopic guidance (Fig 1).
3) Create an insertion hole using reamer along the guide pin to administer the hUC-O and collect an autogenous bone chip (which is later mixed with hUC-O) (Fig 2).
4) Create a tunnel for drug administration along the guide pin and collect an autogenous bone block (which will be inserted as a bone plug following inserting mixture of hUC-O) and insert an 8–12-mm biopsy cannula into the tunnel until it reaches the site of the lesion (Fig 3).
5) Perform curettage to remove the necrotic bone debris and wash the site of the lesion (Fig 4).
6) Mix the autogenous bone chip collected in Step 3 with hUC-O, thrombin glue, collagen putty, hydroxyapatite (HA) and tri-calcium phosphate (TCP) chips (biodegradable and osteoconductive agents).
7) Insert the mixture from Step 6 into the site of the lesion.
8) Fill the remaining space and proximal portion of the bone tunnel with the autogenous bone block collected in Step 4 after performing Step 7.
9) If there is still large amount of space and tunnel remained in distal portion of the tunnel remained after Step 8, insert HA and TCP block may be inserted (Fig 5).
10) Restrict the participant from weight-bearing for 6 weeks. After 6 weeks, the participant is allowed partial weight-bearing using crutches or a walker for 6 weeks.
Characteristics of the hUC-O
An off-white cell suspension is stored in deep freezer (≤−135℃) and can be used for 2 years from the date of manufacture. Vials are stored in a freezer prior to use, thawed for 3 to 5 minutes at 35–37°C, and must be used within 2 hours. A syringe is filled with the whole volume of cell suspension, shaken to achieve an even cell suspension before administration. A vial has a volume of 1 mL and contains 1 ´ 107 human umbilical cord-derived osteoblasts. In this study, hUC-O will be administered into the site of ONFH at a low (1 vial, 1 ´ 107 cells), middle (2 vial, 2 ´ 107 cells), or high dose (4 vial, 4 ´ 107 cells) in the order of group allocation.
Timeline and study protocol
After a volunteer provides written consent to participate in the clinical trial, necessary examinations and tests will be performed within 3 weeks before hUC-O administration (Visit 1) according to the study protocol (Table 1). Participants who meet the inclusion/exclusion criteria in the eligibility assessment will be subjected to CD and hUC-O administration (Visit 2). Participants will be checked for acute adverse events for 3 days after administer hUC-O and visit the facility after 2 (Visit 3), 6 (Visit 4) and 12 (Visit 5) weeks for a safety assessment. The safety assessment will be performed based on the same schedule for all participants with only the administration dose varying.
Table 1
Protocol and timeline for outcome assessments
|
Period
|
Screening
|
Treatmentg)
|
Follow-up 1
|
Follow-up 2
|
Study Completion
/ Dropouti)
|
Visit
|
1
|
2
|
3
|
4
|
5i)
|
Week
|
Within -3
|
0
|
2
|
6
|
12
|
Visit window (days)
|
-
|
-
|
±3
|
±7
|
±7
|
Written consent forma)
|
X
|
|
|
|
|
Demographic information
|
X
|
|
|
|
|
Body weight and height measurement
|
X
|
|
|
|
|
Review medical/operation history
|
X
|
Xh)
|
|
|
|
Review medication history
|
X
|
Xh)
|
|
|
|
Vital signsb)
|
X
|
Xh)
|
X
|
X
|
X
|
Physical examination
|
X
|
Xh)
|
X
|
X
|
X
|
Clinical laboratory testsc)
|
X C-1), C-2)
|
|
X
|
X
|
X C-1)
|
ECG test
|
X
|
|
X
|
X
|
X
|
Pregnancy testd)
|
X
|
|
|
|
X
|
Radiographic examination
|
Xe)
|
|
X
|
X
|
X
|
MRI examination
|
X
|
|
|
|
X
|
ARCO classification
|
X
|
|
|
|
X
|
JIC classification
|
X
|
|
|
|
X
|
Review inclusion/exclusion criteria
|
X
|
X
|
|
|
|
Patient selection
|
|
X
|
|
|
|
Group allocation
|
|
X
|
|
|
|
CD
|
|
X
|
|
|
|
hUC-O administration
|
|
X
|
|
|
|
Pain VAS assessment
|
|
Xh)
|
|
|
X
|
HHS assessment
|
|
Xh)
|
|
|
X
|
WOMAC assessment
|
|
Xh)
|
|
|
X
|
Adverse events assessment
|
|
X f)
|
X
|
X
|
X
|
Check concomitant drug use
|
|
X
|
X
|
X
|
X
|
ECG, electrocardiogram; MRI, magnetic resonance imaging; ARCO, Association Research Circulation Osseous; JIC, Japanese Investigation Committee; CD, core decompression; hUC-O, human umbilical cord derived-osteoblast; VAS, visual analog scale; HHS, Harris hip score; WOMAC, Western Ontario and McMaster Universities
a) Written consent can be obtained from participants before the screening visit.
b) For vital signs, pulse, blood pressure, and body temperature will be measured. At Visit 2, vital signs will be measured before hUC-O administration.
c) For screening tests, test results obtained within 4 weeks after a visit can be used. A retest may also be performed once at the discretion of a researcher during the screening period. The following parameters are assessed during the laboratory tests.
• Blood test: red blood cell (RBC) count, hemoglobin, hematocrit, platelet count, white blood cell (WBC) count, WBC differential count (neutrophil, lymphocyte, monocyte, eosinophil, and basophil), and erythrocyte sedimentation rate (ESR)
•Blood chemistry test: total protein, albumin, total bilirubin, AST, ALT, gamma glutamyl transpeptidase (r-GTP), blood urea nitrogen (BUN), creatinine, glucose, alkaline phosphatase (ALP), total cholesterol, triglyceride, uric acid, c-reactive protein (CRP), panel reactive antibody (PRA)C-1), virus infection test (human immunodeficiency virus antigen/antibody, hepatitis B surface antibody, anti-hepatitis C virus antibody, venereal disease research laboratory [VDRL])C-2)
•Urinalysis: protein (albumin), glucose, ketones, WBC, RBC
d) A serum or urine human chorionic gonadotropin (HCG) test will be performed for women of childbearing age except for those who have been sterilized or are menopausal. Women of childbearing age refer to women who have had their first period, have not been successfully surgically sterilized (via hysterectomy, bilateral tubal ligation, or bilateral oophorectomy), and are not menopausal. Menopause is defined as not having a period for >12 months after the final menstrual period.
e) Test results obtained within 4 weeks after screening can be used.
f) Acute adverse events that occur within 3 days after hUC-O administration will be investigated.
g) Patients will be hospitalized starting 1 day before hUC-O administration and will be monitored throughout the hospitalization period for adverse events.
h) Performed within 3 days and restrict intake of analgesics within 1 day before hUC-O administration.
i) For participants who were withdrawn following the group allocation, the procedures scheduled for the last visit will be performed.
|
To determine the maximal tolerated dose (MTD) of hUC-O, three participants will be sequentially allocated to a group starting with the low-dose group (1 ´ 107 cells) according to the standard 3+3 dose escalation scheme [23]. The first participants in each dose group will be monitored for acute adverse events including dose-limiting toxicity (DLT) for 3 days after the first hUC-O administration. DLT refers to when adverse events related to hUC-O with grade ≥3 are observed based on the definition from the National Cancer Institute-Common Toxicity Criteria (NCI-CTC) version 5.0 [24]. Another two participants will be assigned to the group when dose-limiting toxicity (DLT) does not occur. Up to 18 patients can be enrolled, depending on the development of DLT.
- If none of the three participants experiences DLT, the dose will be increased to the next level.
- If one of the three participants experiences DLT, three participants will be additionally assigned to the same dose group. If one of the six participants (initial three + additional three participants) experience DLT, the dose will be increased to the next level. However, if at least two of the six participants experience DLT, dose escalation will be canceled, and the MTD becomes the previous dose level.
- If at least two of the three participants experience DLT, dose escalation will be canceled, and the MTD becomes the previous dose level.
- If one of the three additional participants show DLT, no additional participants will be assigned to a dose group, and current participants will be monitored for safety.
Participants who do not complete the DLT assessment due to reasons independent of DLT are deemed an inadequate basis for making decisions regarding dose escalation and an MTD assessment and can be replaced by participants who are added to the same dose group.
Safety assessment
Clinically significant abnormal findings from screening or before hUC-O administration (during a screening test) will be recorded as medical history, and those that satisfy the definition of adverse events following hUC-O administration will be recorded as adverse events. The safety assessment will be performed in accordance with the study protocol.
1. Adverse event
Participants will be instructed to report any adverse events, and researchers will examine participants for adverse events through regular or additional visits, interviews, and their history. DLT is included as an adverse event. Any adverse events observed will be reported to the IRB throughout the study period.
2. Laboratory tests
Laboratory tests will be performed for all participants according to the clinical trial schedule to assess the overall health condition of participants. Participants will be instructed to fast (not allowed to drink beverages except for water or eat food within 8 hours before the test) before visiting the facility for blood collection in preparation for laboratory tests. For screening tests (Visit 1), test results obtained in the last 4 weeks may be used instead. One retest may be performed at the discretion of the researcher during the screening period. If a retest has been performed, the results of the retest will be used to determine whether the participant meets the final inclusion and exclusion criteria. The following parameters are assessed during the laboratory tests.
• Blood test
|
Red blood cell (RBC) count, hemoglobin, hematocrit, platelet count, white blood cell (WBC) count, WBC differential count (neutrophil, lymphocyte, monocyte, eosinophil, and basophil), and erythrocyte sedimentation rate (ESR)
|
• Blood chemistry test
|
Total protein, albumin, total bilirubin, AST, ALT, gamma glutamyl transpeptidase (r-GTP), blood urea nitrogen (BUN), creatinine, glucose, alkaline phosphatase (ALP), total cholesterol, triglyceride, uric acid, c-reactive protein (CRP), panel reactive antibody (PRA), virus infection test (HIV antigen/antibody, hepatitis B surface antibody, anti-hepatitis C virus antibody, venereal disease research laboratory [VDRL])
|
• Urinalysis
|
Protein (albumin), glucose, ketones, WBC, RBC
|
Among the blood chemistry tests for viral infections, HIV Antigen/Antibody, hepatitis B Antibody, Anti-hepatitis C antibody, and VDRL tests are performed at Visit 1. Allogeneic immunity (PRA) test is performed at Visit 1 and Visit 5 (Week 12).
3. Vital sign
For vital signs, blood pressure, pulse, breathing rate, and body temperature will be measured. Vital signs are measured before the scheduled test for each visit in accordance with the clinical trial schedule. Participants will be directed to relax for 5 minutes and be seated during the measurement.
4. Physical examination
Each participant will be physically examined through inspection, palpation, percussion, and auscultation in accordance with the clinical trial schedule to check their health conditions and find any adverse events. Physical examination includes examination of the external appearance, head and neck, chest and lungs, heart, abdomen, urinary and reproductive systems, limbs, musculoskeletal system, nervous system, and lymph nodes.
5. ECG test
An ECG test will be performed for all participants at visits 1, 3, 4 and 5. The examiner will determine whether ECG results are normal or abnormal. If the results are abnormal, the examiner will record the clinical significance of the findings on the case report form.
Clinical assessment
1. Pain VAS assessment [18]
Participants will mark on a scale that ranges from “no pain (0)” to “severe pain (10)” their subjective pain level around hip joint. The examiner will determine the number corresponding to the point marked on the scale and record it to one out of 10 decimal place. To examine the changes in pain VAS at different time points after hUC-O administration, pain VAS assessment will be performed at visits 2 and 5.
2. HHS assessment [19]
HHSs will be assessed at visits 2 and 5 to examine the participants’ hip joint function. The highest possible score is 100, and the following domains will be assessed: pain (44 points), gait function (11 points), support devices (11 points), distance walked (11 points), stairs (4 points), putting on shoes (4 points), sitting (5 points), entering public transportation (1 point), presence of deformity (4 points), and hip joint range of motion (5 points).
3. WOMAC score assessment [20]
WOMAC scores will be assessed at visits 2 and 5 to examine the changes in WOMAC scores after hUC-O administration and assess participants’ joint function. WOMAC assesses three domains, namely pain, stiffness, and physical function.
Radiologic assessment
1. Measuring changes in necrotic lesion size
To examine changes in the size of a necrotic lesion in the femoral head following hUC-O administration, the Koo and Kim index will be measured on mid-coronal and mid-sagittal MRI images acquired during visits 1 and 5 [25].
2. ARCO classification [21]
The ARCO classification is an improved version of the Ficat and Arlert classification based on the presence and severity of femoral head collapse and Steinberg classification based on lesion size and progression, which are commonly used to stage ONFH. The ARCO classification determines the site, size, and location of necrosis using radiographs and MRI. Two independent examiners will analyze radiographs and MRI of the hip joint during visit 1 and 5 to examine the changes in the ARCO stage following hUC-O administration. They will then classify the patients who show changes in the ARCO stage following hUC-O administration and femoral head collapse using the ARCO classification. Femoral head collapse corresponds to ARCO stage III.
3. JIC classification [22]
The JIC classification classifies ONFH based on the location of the lesion. It is a radiographic classification method with three major types of ONFH and is based on the location of the lesion in respect to the weight-bearing surface. Two independent examiners will examine the changes in the JIC stage after hUC-O administration by evaluating radiographs and MRI of the femoral region during visit 1 and 5 and classify the lesions according to the JIC classification.