Treatment of Knee Osteoarthritis by Intra-articular Injection of Bone Marrow Mesenchymal Stem Cells

Treatment of Osteoarthritis by Intra-articular Injection of Bone Marrow Mesenchymal Stem Cells

Purpose: To determine the safety, feasibility and effectiveness (clinical and radiological) of intra-articular administration of autologous mesenchymal stem cells (MSCs) in patients with knee osteoarthritis.

Patients and methods

Clinical trial phase I- II, randomized , multicenter , with three treatment arms and 10 patients for each group. The investigators compare the intraarticular injection of hialuronic acid against the administration of two different doses of mesenchymal stem cells with hialuronic acid according to the following scheme:

1. Group A: intra-articular injection of hyaluronic acid (Hyalone®). Single dose.
2. Group B: Low Dosage of MSCs . Intra-articular injection of 10 million autologous mesenchymal progenitor stem cells cultured ex - vivo (cell suspension sterile small volume (5-10 ml ) in a vehicle suitable for intraarticular injection ) followed by an intraarticular injection Hiaurónico Acid ( Hyalone®).
3. Group C : High dose of MSCs. Intra-articular injection of 100 million autologous mesenchymal progenitor stem cells cultured ex - vivo ( cell suspension sterile small volume (5-10 ml ) in a vehicle suitable for intraarticular injection ) followed by an intraarticular injection Hiaurónico Acid (Hyalone®).

The primary endpoint is safety and feasibility. The investigators registered the occurrence of complications and / or adverse effects during the study.

In addition the investigators assess the response to intra-articular infusion of CMM analyzing the following parameters:

• Clinical assessment of pain and function (Baseline, 1, 3, 6 and 12 months since treatment): VAS , WOMAC , KOOS , EuroQol, SF-16, Lequesne , WOMAC , KOOS.
• Radiographic (baseline, 6 and 12 months since treatment): Femorotibial space.
• Radiographic using MRI (baseline, 6 and 12 months since treatment): by assessing the number location of the lesions , cartilage thickness , signal intensity , subchondral bone alteration , volume and WORMS and dGEMRIC protocols.

Study Overview

• Status: Completed
• Conditions: Osteoarthritis
• Intervention / Treatment: Drug: Hyaluronic acid; Biological: 10 million Bone marrow mesenchimal stem cells; Biological: 100 million Bone marrow mesenchimal stem cells

Detailed Description

Purpose: To determine the safety, feasibility and effectiveness (clinical and radiological) of intra-articular administration of autologous mesenchymal stem cells (MSCs) in patients with knee osteoarthritis.

Patients and methods

Clinical trial phase I- II, randomized , multicenter , with three treatment arms and 10 patients for each group. The investigators compare the intraarticular injection of hialuronic acid against the administration of two different doses of mesenchymal stem cells with hialuronic acid according to the following scheme:

1. Group A: intra-articular injection of hyaluronic acid (Hyalone®). Single dose.
2. Group B: Low Dosage of MSCs . Intra-articular injection of 10 million autologous mesenchymal progenitor stem cells cultured ex - vivo (cell suspension sterile small volume (5-10 ml ) in a vehicle suitable for intraarticular injection ) followed by an intraarticular injection Hiaurónico Acid ( Hyalone®).
3. Group C : High dose of MSCs. Intra-articular injection of 100 million autologous mesenchymal progenitor stem cells cultured ex - vivo ( cell suspension sterile small volume (5-10 ml ) in a vehicle suitable for intraarticular injection ) followed by an intraarticular injection Hiaurónico Acid (Hyalone®).

The autologous mesenchymal stem cells are obtained from the iliac crest and cultured ex vivo under local anesthesia and sedation.

The primary endpoint is safety and feasibility. The investigators registered the occurrence of complications and / or adverse effects during the study.

In addition the investigators assess the response to intra-articular infusion of CMM analyzing the following parameters:

• Clinical assessment of pain and function (Baseline, 1, 3, 6 and 12 months since treatment): VAS , WOMAC , KOOS , EuroQol, SF-16, Lequesne , WOMAC , KOOS.
• Radiographic (baseline, 6 and 12 months since treatment): Femorotibial space.
• Radiographic using MRI (baseline, 6 and 12 months since treatment): by assessing the number location of the lesions , cartilage thickness , signal intensity , subchondral bone alteration , volume and WORMS and dGEMRIC protocols.

All patients met the following inclusion and exclusion criteria:

Inclusion Criteria:

• Males and females between 50 and 80 year old.
• Diagnosis of knee OA according to the criteria of osteoarthritis of the ACR (American College of Rheumatology).
• Joint pain equal or greater than 2.5 points on the visual analogue scale (VAS).
• Radiological Classification: Kellgren-Lawrence scale greater or equal to 2.
• Body mass index between 20 and 35 kg/m2.
• Ability to follow during the study period.

Exclusion Criteria:

• Bilateral Osteoarthritis of the Knee requiring treatment in both knees.
• Previous diagnosis of polyarticular disease.
• Severe mechanical deformation.
• Arthroscopy during the previous 6 months.
• Intraarticular infiltration of hyaluronic acid in the last 6 months.
• Systemic autoimmune rheumatic disease.
• Poorly controlled diabetes mellitus.
• Blood dyscrasias.
• Immunosuppressive or anticoagulant treatments.
• Treatment with corticosteroids in the 3 months prior to inclusion in the study.
• NSAID therapy within 15 days prior to inclusion in the study.
• Patients with a history of allergy to penicillin or streptomycin.
• Allergy to hyaluronic acid or poultry proteins.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Spain
  • Castilla y León
    • Salamanca, Castilla y León, Spain, 37007
      • Traumatology department. Complejo Hospitalario de Salamanca
  • Navarra
    • Pamplona, Navarra, Spain, 31008
      • Orthopaedic and traumatology department. Clínica Universidad de Navarra

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Males and females between 50 and 80 year old.
• Diagnosis of knee OA according to the criteria of osteoarthritis of the ACR (American College of Rheumatology).
• Joint pain equal or greater than 2.5 points on the visual analogue scale (VAS).
• Radiological Classification: Kellgren-Lawrence scale greater or equal to 2.
• Body mass index between 20 and 35 kg/m2.
• Ability to follow during the study period.

Exclusion Criteria:

• Bilateral Osteoarthritis of the Knee requiring treatment in both knees.
• Previous diagnosis of polyarticular disease.
• Severe mechanical deformation.
• Arthroscopy during the previous 6 months.
• Intraarticular infiltration of hyaluronic acid in the last 6 months.
• Systemic autoimmune rheumatic disease.
• Poorly controlled diabetes mellitus.
• Blood dyscrasias.
• Immunosuppressive or anticoagulant treatments.
• Treatment with corticosteroids in the 3 months prior to inclusion in the study.
• NSAID therapy within 15 days prior to inclusion in the study.
• Patients with a history of allergy to penicillin or streptomycin.
• Allergy to hyaluronic acid or poultry proteins.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Hialuronic acid; Single intraarticular injection of Hyaluronic acid (Hyal One)	Drug: Hyaluronic acid; Single intraarticular injection of Hyaluronic acid (Hyal One); Other Names: HyalOne
Active Comparator: Hyaluronic acid and MSC 10; Single intraarticular injection of Hyaluronic acid (Hyal One) 10 million Bone marrow mesenchimal stem cells	Drug: Hyaluronic acid; Single intraarticular injection of Hyaluronic acid (Hyal One); Other Names: HyalOne; Biological: 10 million Bone marrow mesenchimal stem cells; 10 million of Bone marrow mesenchimal stem cells
Active Comparator: Hyaluronic acid AND MSC 100; Single intraarticular injection of Hyaluronic acid (Hyal One) 100 million Bone marrow mesenchimal stem cells	Drug: Hyaluronic acid; Single intraarticular injection of Hyaluronic acid (Hyal One); Other Names: HyalOne; Biological: 100 million Bone marrow mesenchimal stem cells; 100 million of Bone marrow mesenchimal stem cells

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Baseline Visual analogue scale (VAS)	Baseline Visual analogue scale (VAS)	prior to the initial dose on day 1
Baseline value of knee injury and osteoarthritis outcome score (Koos).	Prior to the intervention on day 1 value of knee injury and osteoarthritis outcome score (Koos).	Prior to the intervention on day 1
Baseline Western Ontario and McMaster Universities Osteoarthritis Index score (WOMAC).	Prior to the intervention on day 1 Western Ontario and McMaster Universities Osteoarthritis Index score (WOMAC).	Prior to the intervention on day 1
Baseline SF-36 value	Prior to the intervention on day 1 SF-36 value	Prior to the intervention on day 1
Baseline euroquol 5D value	Pretreatment euroquol 5D value	Prior to the intervention on day 1
Baseline Lequesne index	Prior to the intervention on day 1 Lequesne index	Prior to the intervention on day 1
Baseline femorotibial distance	Prior to the intervention femoritibial distance on rosenberg x-ray view	Prior to the intervention
Number of Participants with Serious and Non-Serious Adverse Events Number of Participants with Serious and Non-Serious Adverse Events Number of Participants with Serious and Non-Serious Adverse Events	During the follow up	Follow up
Visual analogue scale (VAS) at on month	Visual analogue scale (VAS) at on month	1 month
Visual analogue scale (VAS) at 3 months	Visual analogue scale (VAS) at 3 months	3 months
Visual analogue scale (VAS) at 6 months	Visual analogue scale (VAS) at 6 months	6 months
Visual analogue scale (VAS) at 12 months	Visual analogue scale (VAS) at 12 months	12 months
Value of knee injury and osteoarthritis outcome score (Koos) at 1 month	Value of knee injury and osteoarthritis outcome score (Koos) at 1 month	1 month
Value of knee injury and osteoarthritis outcome score (Koos) at 3 month	Value of knee injury and osteoarthritis outcome score (Koos) at 3 month	3 Months
Value of knee injury and osteoarthritis outcome score (Koos) at 6 month	Value of knee injury and osteoarthritis outcome score (Koos) at 6 month	6 months
Value of knee injury and osteoarthritis outcome score (Koos) at 12 months	Value of knee injury and osteoarthritis outcome score (Koos) at 12 months	12 months
Western Ontario and McMaster Universities Osteoarthritis Index score (WOMAC) at 1 month	Western Ontario and McMaster Universities Osteoarthritis Index score (WOMAC) at 1 month	1 month
Western Ontario and McMaster Universities Osteoarthritis Index score (WOMAC) at 3 month	Western Ontario and McMaster Universities Osteoarthritis Index score (WOMAC) at 1 month	3 months
Western Ontario and McMaster Universities Osteoarthritis Index score (WOMAC) at 6 month	Western Ontario and McMaster Universities Osteoarthritis Index score (WOMAC) at 6 month	6 months
Western Ontario and McMaster Universities Osteoarthritis Index score (WOMAC) at 12 months	Western Ontario and McMaster Universities Osteoarthritis Index score (WOMAC) at 12 months	12 months
SF-36 value at 1 month	SF-36 value	1 month
SF 36 value at 3 months	SF 36 value at 3 months	3 months
SF 36 value at 6 months	SF 36 value at 6 months	6 months
SF 36 value at 12 months	SF 36 value at 12 months	12 months
Euroquol 5D value at 1 month	Euroquol 5D value at 1 month	1 MOnth
Euroquol 5D value at 3 months	Euroquol 5D value at 3 months	3 months
Euroquol 5D value at 6 months	Euroquol 5D value at 6 months	6 months
Euroquol 5D value at 12 months	Euroquol 5D value at 12 months	12 months
Lequesne index at 1 month	Lequesne index at 1 month	1 month
Lequesne index at 3 months	Lequesne index at 3 months	3 months
Lequesne index at 6 months	Lequesne index at 6 months	6 months
Lequesne index at 12 months	Lequesne index at 12 months	12 months
Femorotibial distance at 6 months	Femorotibial distance at 6 months	6 months
Femorotibial distance at 12 months	Femorotibial distance at 12 months	12 months
Baseline MRI WORMS protocol	Prior to the intervention MRI WORMS protocol	Prior to the intervention
MRI WORMS protocol score at 6 months	MRI WORMS protocol score at 6 months	6 months
MRI WORMS protocol score at 12 months	MRI WORMS protocol score at 12 months	12 months

Collaborators and Investigators

• Sponsor: Clinica Universidad de Navarra, Universidad de Navarra
• Investigators: Principal Investigator: José Lamo-Espinosa, MD, Clinica Universidad de Navarra; Study Director: Felipe Prosper, MD PhD, Clinica Universidad de Navarra; Principal Investigator: Juan Blanco, MD PhD, University of Salamanca

Publications and helpful links

General Publications

• Lamo-Espinosa JM, Prosper F, Blanco JF, Sanchez-Guijo F, Alberca M, Garcia V, Gonzalez-Vallinas M, Garcia-Sancho J. Long-term efficacy of autologous bone marrow mesenchymal stromal cells for treatment of knee osteoarthritis. J Transl Med. 2021 Dec 11;19(1):506. doi: 10.1186/s12967-021-03160-2.
• Lamo-Espinosa JM, Mora G, Blanco JF, Granero-Molto F, Nunez-Cordoba JM, Lopez-Elio S, Andreu E, Sanchez-Guijo F, Aquerreta JD, Bondia JM, Valenti-Azcarate A, Del Consuelo Del Canizo M, Villaron EM, Valenti-Nin JR, Prosper F. Intra-articular injection of two different doses of autologous bone marrow mesenchymal stem cells versus hyaluronic acid in the treatment of knee osteoarthritis: long-term follow up of a multicenter randomized controlled clinical trial (phase I/II). J Transl Med. 2018 Jul 31;16(1):213. doi: 10.1186/s12967-018-1591-7.
• Lamo-Espinosa JM, Mora G, Blanco JF, Granero-Molto F, Nunez-Cordoba JM, Sanchez-Echenique C, Bondia JM, Aquerreta JD, Andreu EJ, Ornilla E, Villaron EM, Valenti-Azcarate A, Sanchez-Guijo F, Del Canizo MC, Valenti-Nin JR, Prosper F. Intra-articular injection of two different doses of autologous bone marrow mesenchymal stem cells versus hyaluronic acid in the treatment of knee osteoarthritis: multicenter randomized controlled clinical trial (phase I/II). J Transl Med. 2016 Aug 26;14(1):246. doi: 10.1186/s12967-016-0998-2.

Helpful Links

• University clinic of navarre trial information

Study record dates

Study Major Dates

• Study Start: May 1, 2012
• Primary Completion (Actual): November 1, 2014
• Study Completion (Actual): February 1, 2015

Study Registration Dates

• First Submitted: November 12, 2013
• First Submitted That Met QC Criteria: April 23, 2014
• First Posted (Estimate): April 25, 2014

Study Record Updates

• Last Update Posted (Actual): October 24, 2017
• Last Update Submitted That Met QC Criteria: October 23, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Keywords: Osteoarthritis; Knee; Mesenchimal stem cell
• Additional Relevant MeSH Terms: Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Arthritis; Osteoarthritis; Physiological Effects of Drugs; Immunologic Factors; Protective Agents; Adjuvants, Immunologic; Viscosupplements; Hyaluronic Acid
• Other Study ID Numbers: CMM/ART; 2009-017624-72 (EudraCT Number)