Human ECM Implanted Within Microfracture Interstices & the Cartilage Defect in the Knee to Regenerate Hyaline Cartilage

NCT05082831 | Terminated Phase 1 DMC FDA Drug

• 1 other identifier: HST003-ORT-001-CR
• Study Type: interventional
• Target: 1
• Locations: 1 country
• Sites: 5

Brief Summary

HST003 is a human extracellular matrix designed for injection into the subchondral bone following microfracture surgery by an injection into the interstices created by the surgical awl and filling the full defect to help restore-regenerate hyaline cartilage to a pre-injury state. In this Phase 1/2 clinical trial, we will be addressing the knee joint in conjunction with microfracture surgery. HST003 is human extracellular matrix secreted by human dermal fibroblasts under hypoxic conditions. The various matrix proteins produce a combination structural scaffold in addition to the natural secreted glycoproteins such as lubricin, fibronectin, laminins, hyaluronic acid, and collagens - all critical components of cartilage, particularly hyaline cartilage. This Phase 1/2 study will help design additional studies to support FDA approval for the use of HST003 in focal cartilage defects in the knee resulting from recent traumatic injury.

Conditions

Articular Cartilage Disorder of Knee; Cartilage Damage; Microfractures

Keywords

Hyaline Cartilage; Cartilage, Articular; Arthroscopic, Subchondral; Extracellular Matrix Proteins; Extracellular Matrix; Arthroscopic Subchondral Bone Microfracture

Outcome Measures

Primary Outcomes (4)

• Assessment of joint pain equal to or lesser than microfracture alone, and equal or greater function, as measured using the KOOS (Knee Injury and Osteoarthritis Outcome Score) questionnaire

  The KOOS (Knee Injury and Osteoarthritis Outcome Score) questionnaire will be completed at Screening (only questions 5-9 of the pain sub-form) and at Day 0 (before surgery), 42, 84, 168 and 365. Change from baseline in the KOOS pain sub-score will be compared between the study and control groups to test the hypothesis that use of HST003 in arthroscopic microfracture surgery is associated with an equal or lesser pain score than control. The questionnaire has five separately scored subscales: Pain, Function in Daily Living (ADL), Function in Sport and Recreation, Other Symptoms, and Knee-Related Quality of Life (QOL). Each question is assigned a score (0-4) and a normalized score is calculated for each subscale (100 indicates no symptoms and 0 indicates extreme symptoms). Higher scores represent higher/better levels of function.

  Day 168 (week 24, Visit 8)

• Assessment of joint pain equal to or lesser than microfracture alone, and equal or greater function, as measured using the validated IKDC (International Knee Documentation Committee) questionnaire

  The IKDC (International Knee Documentation Committee) questionnaire will be completed at Day 0 (before surgery), 42, 84, 168, 365 and 730. Change from baseline in the IKDC score will be compared between the study and control groups to test the hypothesis that use of HST003 in arthroscopic microfracture surgery is associated with an equal or greater knee function score than control. Scores are obtained by summing the individual items, then transforming the crude total to a scaled number that ranges from 0 to 100. This final number is interpreted as a measure of function with higher scores representing higher levels of function. A score of 100 is interpreted to mean no limitation with activities of daily living or sports activities and the absence of symptoms.

  Day 168 (week 24, Visit 8)

• Assessment of joint pain equal to or lesser than microfracture alone, and equal or greater function, as measured using the Western Ontario and McMaster Universities Arthritis Index (WOMAC) questionnaire between baseline and month 6

  Assessment of joint pain equal to or lesser than microfracture alone, and equal or greater function, as measured using the Western Ontario and McMaster Universities Arthritis Index (WOMAC) questionnaire between baseline and Month 6. The WOMAC measures five items for pain (score range 0-20), two for stiffness (score range 0-8), and 17 for functional limitation (score range 0-68). Lower scores represent more pain, stiffness, and function values.

  Day 168 (week 24, Visit 8)

• Assessment of joint pain equal to or lesser than microfracture alone, and equal or greater function, as measured using the Visual Analog Scale (VAS) questionnaire between baseline and month 6

  Assessment of joint pain equal to or lesser than microfracture alone, and equal or greater function, as measured using the Visual Analog Scale (VAS) questionnaire between baseline and Month 6. Scores are recorded by making a handwritten mark on a 10-cm line that represents a continuum between "no pain" and "worst pain."

  Day 168 (week 24, Visit 8)

Secondary Outcomes (5)

• Presence of new hyaline or fibrous cartilage formation within the repaired defects as visualized by MRI

  Day 168 (week 24, Visit 8) and Day 365 (week 52, Visit 9)

• Investigator assessment of functional Range of Motion (ROM) including overall strength in the knee

  Day 84, Day 168, and Day 365.

• An independent central radiology reviewer from the Image Analysis Group (IAG) will read the MRIs, blinded. The reviewer's scores will be used in the efficacy assessment.

  Day 168 (week 24, Visit 8) and Day 365 (week 52, Visit 9)

• An independent central radiologist from the Image Analysis Group (IAG) will blindly read the MRIs evaluate cartilage quality within the repaired defects.

  Day 168 (week 24, Visit 8) and Day 365 (week 52, Visit 9)

• Participant assessment of Activities of Daily Living (ADL).

  Day 168 (week 24, Visit 8) and Day 365 (week 52, Visit 9)

Study Arms (2)

microfracture surgery + HST003

ACTIVE COMPARATOR

This is an Intervention Model where all patients who are identified/confirmed candidates for microfracture surgery will be enrolled to receive the microfracture surgery (standard of care). Ten (10) patients will be randomized to receive the study intervention (HST003). HST003 will be injected into the microfracture defects (interstices) and fill the remainder of the defect to the cartilage margin following surgery.

Biological: microfracture surgery + HST003

microfracture surgery only

NO INTERVENTION

This is an Intervention Model where all patients who are identified/confirmed candidates for microfracture surgery will be enrolled to receive the microfracture surgery (standard of care). Ten (10) patients will be randomized to receive the microfracture surgery (standard of care).

Interventions

microfracture surgery + HST003 BIOLOGICAL

This is an Intervention Model where all patients who are identified/confirmed candidates for microfracture surgery will be enrolled to receive the microfracture surgery (standard of care). Ten (10) patients will be randomized to receive the study intervention (HST003). HST003 will be injected into the microfracture defects (interstices) and fill the remainder of the defect to the cartilage margin following surgery. The primary purpose of the study is to compare the two groups: microfracture surgery + HST003 as compared to the microfracture surgery only group.

microfracture surgery + HST003

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• \- Age
• Participant must be ≥ 18 years and ≤ to 50 years of age (18-50), at the time of signing the informed consent.
• Type of Participant and Disease Characteristics
• Patients who are "healthy" as determined by medical evaluation including medical history, physical exam, laboratory tests, no thyroid conditions, and no history of cancer, etc.
• Patients with controlled hypertension defined as systolic blood pressure less than 140mmHg and diastolic blood pressure less than 90mmHg.
• Patients with well controlled diabetes mellitus type 2 defined as an HbA1C of less than 6.5%.
• Patients that have hematological parameters as follows: hematocrit ≥ 28.0%, white blood cell count ≤ 14,000/mm3, platelet count ≥ 50,000/mm3, creatinine
• ≤ 2.0mg/dL and International Normalized Ration (INR) ≤ 1.6.
• Patients that have been diagnosed with a symptomatic (knee pain, effusion, and limitation of activity due to the lesion) cartilage lesion of the medial or lateral femoral condyle and have failed to respond to more conservative pharmacologic or non-pharmacologic treatments. Acute, isolated, traumatic defects are permitted in the study.
• A cartilage lesion on the medial or lateral femoral condyle that is Grade III or IV on the Outerbridge scale, and having size of 2 cm2 - 4 cm2 as detected by MRI or recent arthroscopy if conducted in connection with this acute knee injury.
• Intact ligaments - including intact (i) anterior cruciate ligament (ACL), (ii) lateral collateral ligament (LCL), (iii) posterior cruciate ligament (PCL), and (iv) medial collateral ligament (MCL). No concurrent ligament surgery is permitted.
• Near normal (within 3 degrees of center) hip to ankle coronal alignment on plain radiographs. Per Schedule of Activities, X-ray of knee will be taken at screening visit.
• Participant who is medically able to undergo knee arthroscopy and participate in the postoperative therapy protocol, including a period (up to 4 to 6 weeks) of nonweight bearing movement.
• If participant has had prior surgery in the index knee but is stable on exam, then the participant can be included in the study (e.g., stable ACL reconstruction, diagnostic arthroscopy, plica/scar debridement, meniscus debridement less than 50%, and chondroplasty are permitted). No prior microfracture surgery in the index knee are permitted.
• Tibial lesions on the same side as the femoral condyle lesion being treated up to Grade I or II Outerbridge grade is permitted.

You may not qualify if:

• Medical Conditions
• History of substantial (greater than or equal to 50%) meniscal repair or a meniscectomy.
• Known, recent (within one month of screening) history of bacterial infection regardless of body location.
• Prior surgical repair of the site (femoral condyle) intended to undergo microfracture surgery. No prior microfracture of the index knee is permitted.
• Single Assessment Numeric Evaluation (SANE) of greater than 80.
• Prior surgery of the contralateral knee within the last 3 months (since opposite knee needs to be intact for the non-weightbearing period post-op).
• Has vascular disorders such as varicose veins or peripheral arterial disease or neurological disorders (e.g., neuropathy affecting the index lower limb).
• Known allergy to anesthetics used in the study.
• Presence of significantly uncontrolled hypertension defined as systolic blood pressure more than or equal to 140mmHg and diastolic blood pressure more than or equal to 90mmHg.
• Severely uncontrolled diabetes mellitus, defined as HbA1C of 6.5% or more.
• Patients with results from any of the screening blood work to include: complete blood count, Prothrombin Time (PT)/Partial Thromboplastin Time (PTT)/INR, liver function, and creatinine) that exceeds 1.5 times the upper limit of normal or below 0.5 times the lower limit of normal.
• Patients with significant renal or hepatic impairment, as indicated by: Aspartate aminotransferase (AST), alanine aminotransferase (ALT), or alkaline phosphatase (ALP) greater than (\>) 3 times the upper limit of normal (ULN); total bilirubin \>1.5 times ULN (except in case of Gilbert's syndrome); creatinine \>1.5 times ULN; hemoglobin less than (\<5.5) millimole per liter (mmol/L), white blood cell count (WBC) \<2.5 \* 10\^9 per liter, or platelets \<75 \*10\^9 per liter).
• Recent (within 1 year from screening) history of thromboembolism.
• Known heart failure New York Heart Association (NYHA) class III or higher.
• Current malignancy or treatment for malignancy within the past 5 years, with the exception of non-melanoma skin cancer, or carcinoma in situ events.

Sponsors & Collaborators

• Histogen: lead
• United States Department of Defense: collaborator

Study Sites (5)

Site 002

Vail, Colorado, 81657, United States

Location

Site 003

Bradenton, Florida, 34209, United States

Location

Site 001

Bethesda, Maryland, 20814, United States

Location

Site 005

State College, Pennsylvania, 16801, United States

Location

Site 004

Houston, Texas, 77027, United States

Location

MeSH Terms

Conditions

Fractures, Stress

Condition Hierarchy (Ancestors)

Fractures, Bone; Wounds and Injuries

Study Officials

• Mark A Hubka

  Histogen

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Masking Details: Patients will be randomized on the treatment day (Visit 2 per Schedule of Activities below) to undergo microfracture surgery with or without HST003 injection into the interstices and defect post-microfracture procedure. Each clinical site will have a study drug dispenser who will be responsible for randomizing the patient via the IWRS and will know whether the patient will be receiving HST003 or not, maintaining the blinding until the surgeon is approaching the end of the procedure.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: This is an Intervention Model where all patients who are identified/confirmed candidates for microfracture surgery will be enrolled to receive the microfracture surgery (standard of care). Ten (10) patients will be randomized to receive the study intervention (HST003). HST003 will be injected into the microfracture defects (interstices) and fill the remainder of the defect to the cartilage margin following surgery. The primary purpose of the study is to compare the two groups: microfracture surgery + HST003 as compared to the microfracture surgery only group.

Study Record Dates

• First Submitted: June 8, 2021
• First Posted: October 19, 2021
• Study Start: November 15, 2021
• Primary Completion: December 16, 2022
• Study Completion: January 16, 2023
• Last Updated: January 19, 2023

Record last verified: 2023-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (5)