**g.Use of MSC alone or MSC with a scaffold for intra-articular injection in OA**:

When MSCs are injected intra-articularly alone, MSCs scatter widely in the joint, making it impossible to obtain consistent local concentration at the site of cartilage defect. Hence, with a hope to enhance their efficacy in cartilage regeneration, MSC implantation using scaffolds is being attempted in different clinical trials so that the cells are delivered to the site of interest. Compared to direct intra-articular injection, MSC delivery via a scaffold affords more control of proliferation, matrix production, and self-renewal which may help in the regeneration/repair of degenerated or damaged articular cartilage. Different scaffolds have been designed as the delivery system for the repair of articular cartilage. The different scaffolds which can be used are either made of poly-lactic-coglycolic acids (PLGA) [115], collagen [116], gelatin [117], tricalcium (TCP) [118], poly-lactic acid (PLA) [115], hyaluronic acid (HA) [119], poly-glycolic acid (PGA), or fibrin glue [120]. HA has been used frequently for implantation of MSCs into the joint. Many clinical studies (**Table 2**) have used HA as scaffold along with MSCs for implantation of the cells. Cartistem®, an approved drug by the Korean FDA for knee OA, is a combination of human umbilical cord blood-derived MSCs and sodium hyaluronate which is directly implanted at the site of cartilage injury into the joint by arthroscopy [96, 121]. Hence, cells with scaffold are the ideal combination for intra-articular delivery for cartilage degeneration. However, further studies are necessary to find optimal implantation vehicles that can result in the regeneration of articular cartilage.

### **8.3 Clinical trials in India**

Few clinical trials using autologous or allogeneic MSCs or mononuclear stem cells in OA have been conducted in India. The trials registered in the Clinical Trials Registry of India are the two trials done by Stempeutics (one phase II trial completed and the other phase III trial ongoing). However, one published trial by Bansal et al. [122] for the single-arm study was done in India in which a total of 10 patients were treated with AD-MSCs. The patients were evaluated for safety, WOMAC, 6-minute walk test (6MWT), and MRI for cartilage thickness. The patients were followed up for 2 years. The total WOMAC and its subscale scores and 6MWT were significantly improved at all-time points till 2 years of follow-up. Cartilage thickness as determined by MRI improved by at least 0.2 mm in six patients, was unchanged in two patients, and decreased by at least 0.2 mm in two patients. The authors concluded that the procedure demonstrated a strong safety profile with no severe adverse events or complications reported.

*Update on Mesenchymal and Induced Pluripotent Stem Cells*

cells) of allogeneic BMMSCs were used in a total of 60 patients. At 1 year of follow-up, the lower doses of 25 million had shown improvement in pain levels and function as compared to placebo and baseline. However in a study by Jo et al. [101], 18 patients were injected with autologous AD-MSCs in three different doses: 10, 50, and 100 million cells. At 2 years of follow-up, significant improvement in the Knee Society clinical rating system (KSS), Knee Injury and Osteoarthritis Outcome Score (KOOS), and VAS scores was seen in the highest dose of 100 million cells. As can be seen, most of the studies are single-arm studies without any control arm. Hence, to determine the most efficacious dose in OA,

more randomized controlled, dose-finding clinical trials are required.

**e.Selection of endpoints for the conduct of clinical trial**: The FDA 2018 draft guidance document for OA regarding the development of structural endpoints for the development of drugs, devices, and biological products for treatment states that approvals for OA to date have been based on patient-reported outcome measures that assess pain and function. For the development of new product in OA, the goal of treatment should be inhibition of structural damage or targeting the underlying pathophysiology associated with OA or significantly delay the complications of joint failure and the need for joint replacement and also to reduce the deterioration of function and worsening of pain. All of the above may be taken into consideration for the development of endpoints for the study in OA [112].

Recently a meta-analysis was done to evaluate the different endpoints used to see the therapeutic efficacy and safety of MSCs for the treatment of patients with knee osteoarthritis [113]. Five hundred eighty-two patients in 11 randomized controlled trials were included in this meta-analysis. It showed that MSC treatment significantly improved VAS and International Knee Documentation Committee (IKDC) scores after 24 months of follow-up compared to controls. MSC therapy also showed significant improvement in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Lequesne algofunctional indices (Lequesne), Lysholm knee scale (Lysholm), and Tegner activity scale (Tegner) at 12 or 24 months of follow-up. Hence, all the endpoints used currently for evaluation of efficacy in OA have shown significant improvement in different

**f. MRI to evaluate cartilage regeneration**: MRI has emerged as the leading method of imaging soft tissue structures around joints. An ideal MRI study for the cartilage should provide an accurate assessment of cartilage thickness and volume, show morphologic changes of the cartilage surface, show internal cartilage signal changes, and allow evaluation of the subchondral bone for signal abnormalities. Also, it would be desirable for MRI to provide an evaluation of the underlying cartilage physiology, including providing information about the status of the glycosaminoglycan (GAG) and collagen matrices [114]. But, in actual, there is an absence of a standard system by MRI to evaluate cartilage regeneration. Many studies as given in **Table 2** that have used MRI to evaluate cartilage regeneration are only qualitative. It is recommended to use validated imaging outcomes for cartilage regeneration for scientifically validating cell-based therapies, thus advancing the field. The most common parameters used for evaluation of cartilage regeneration by MRI are cartilage thickness in different points in all the compartments of the joint [97], cartilage volume [101], whole-organ magnetic resonance imaging score (WORMS) [43, 48], T2 relaxation time mapping [78, 83, 85, 95, 98], MRI Osteoarthritis Knee Score (MOAKS) score [88, 103], magnetic

resonance observation of cartilage repair tissue (MOCART) score [88],

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clinical trials:

#### **8.4 Stempeutics Research experience in osteoarthritis of the knee joint**

The off-the-shelf allogeneic, pooled BMMSC product developed by Stempeutics has completed one phase II clinical trial [43] and currently ongoing phase III trial in knee OA. In our completed phase II trial, we included patients of idiopathic OA in grade 2 or 3 of Kellgren and Lawrence radiographic criteria; patients who had self-reported difficulty in at least one of the following activities attributed to knee pain, lifting and carrying groceries, walking 400 m, getting in and out of a chair, or going up and down stairs; and patients who had been on stable medication, including nonsteroidal anti-inflammatory drugs/opioid analgesics for the past 3 months and in the age group of 40–70 years. All the criteria have to be present before being included in the study [43].

#### *8.4.1 Phase II study in patients with osteoarthritis of the knee joint*

The phase II results of Stempeucel® in OA patients have been published [43]. Briefly, it was a double-blind, randomized, placebo-controlled, dose-finding study. In this study, 60 OA patients were randomized to receive different doses of Stempeucel®, 25, 50, 75, and 150 million cells or placebo. Stempeucel® was administered intra-articularly (IA) to the knee joint followed by 2 ml of hyaluronic acid (20 mg). The subjects were followed up for 2 years and were evaluated for safety parameters including AEs, and for efficacy parameters, VAS for pain, Intermittent and Constant Osteoarthritis Pain (ICOAP), WOMAC (total score and its subscales), and MRI were done to evaluate the WORMS score. The intra-articular administration of Stempeucel® was safe with knee pain and swelling as the most common AEs. Clinically relevant improvement in a persistent manner was seen in 25 million dose group in all subjective parameters (VAS, ICOAP, and WOMAC scores) (**Figures 2–4**). WORMS of MRI knee did not reveal any difference from the baseline and placebo group. It was concluded that intra-articular administration of Stempeucel® is safe and 25 million dose may be the most effective among the doses tested.

Currently, we are conducting a phase III trial in OA of the knee joint. This is a randomized, double-blind, multicentric, placebo-controlled study assessing the efficacy and safety of intra-articular administration of Stempeucel® in patients with osteoarthritis of the knee joint. One hundred and forty-six patients will be

#### **Figure 2.**

*Visual analog scale values. Data presented as mean value ± SD; C1 = cohort 1; C2 = cohort 2; 25M, 50M, 75M, 150M = 25, 50, 75, 150 million cells, respectively; 1M, 3M, 6M, 12M = 1, 3, 6, 12 months, respectively.*

**71**

**Figure 3.**

India (CTRI/2018/09/015785).

*and McMaster Universities Osteoarthritis Index.*

*The Role of Mesenchymal Stromal Cells in the Management of Osteoarthritis of the Knee*

randomized to stem cell and placebo arm in a ratio of 1:1. Seventy-three patients will receive Stempeucel® (25 million) followed by 2 ml of hyaluronan, and 73 patients will receive only intra-articular injection of 2 ml of placebo followed by 2 ml of hyaluronan. The patients will be followed up for a total of 2 years after IMP administration. The details of the study are found in the Clinical Trials Registry of

*WOMAC results. WOMAC: (A, B) composite; (C, D) pain; (E, F) stiffness; and (G, H) physical function. Data presented as mean value ± SD; C1 = cohort 1; C2 = cohort 2; 25M, 50M, 75M, 150M = 25, 50, 75, 150 million cells, respectively; 1M, 3M, 6M, 12M = 1, 3, 6, 12 months, respectively; WOMAC = Western Ontario* 

*DOI: http://dx.doi.org/10.5772/intechopen.86016*

#### **Figure 3.**

*Update on Mesenchymal and Induced Pluripotent Stem Cells*

included in the study [43].

among the doses tested.

**8.4 Stempeutics Research experience in osteoarthritis of the knee joint**

*8.4.1 Phase II study in patients with osteoarthritis of the knee joint*

The off-the-shelf allogeneic, pooled BMMSC product developed by Stempeutics has completed one phase II clinical trial [43] and currently ongoing phase III trial in knee OA. In our completed phase II trial, we included patients of idiopathic OA in grade 2 or 3 of Kellgren and Lawrence radiographic criteria; patients who had self-reported difficulty in at least one of the following activities attributed to knee pain, lifting and carrying groceries, walking 400 m, getting in and out of a chair, or going up and down stairs; and patients who had been on stable medication, including nonsteroidal anti-inflammatory drugs/opioid analgesics for the past 3 months and in the age group of 40–70 years. All the criteria have to be present before being

The phase II results of Stempeucel® in OA patients have been published [43]. Briefly, it was a double-blind, randomized, placebo-controlled, dose-finding study. In this study, 60 OA patients were randomized to receive different doses of Stempeucel®, 25, 50, 75, and 150 million cells or placebo. Stempeucel® was administered intra-articularly (IA) to the knee joint followed by 2 ml of hyaluronic acid (20 mg). The subjects were followed up for 2 years and were evaluated for safety parameters including AEs, and for efficacy parameters, VAS for pain, Intermittent and Constant Osteoarthritis Pain (ICOAP), WOMAC (total score and its subscales), and MRI were done to evaluate the WORMS score. The intra-articular administration of Stempeucel® was safe with knee pain and swelling as the most common AEs. Clinically relevant improvement in a persistent manner was seen in 25 million dose group in all subjective parameters (VAS, ICOAP, and WOMAC scores) (**Figures 2–4**). WORMS of MRI knee did not reveal any difference from the baseline and placebo group. It was concluded that intra-articular administration of Stempeucel® is safe and 25 million dose may be the most effective

Currently, we are conducting a phase III trial in OA of the knee joint. This is a randomized, double-blind, multicentric, placebo-controlled study assessing the efficacy and safety of intra-articular administration of Stempeucel® in patients with osteoarthritis of the knee joint. One hundred and forty-six patients will be

*Visual analog scale values. Data presented as mean value ± SD; C1 = cohort 1; C2 = cohort 2; 25M, 50M, 75M,* 

*150M = 25, 50, 75, 150 million cells, respectively; 1M, 3M, 6M, 12M = 1, 3, 6, 12 months, respectively.*

**70**

**Figure 2.**

*WOMAC results. WOMAC: (A, B) composite; (C, D) pain; (E, F) stiffness; and (G, H) physical function. Data presented as mean value ± SD; C1 = cohort 1; C2 = cohort 2; 25M, 50M, 75M, 150M = 25, 50, 75, 150 million cells, respectively; 1M, 3M, 6M, 12M = 1, 3, 6, 12 months, respectively; WOMAC = Western Ontario and McMaster Universities Osteoarthritis Index.*

randomized to stem cell and placebo arm in a ratio of 1:1. Seventy-three patients will receive Stempeucel® (25 million) followed by 2 ml of hyaluronan, and 73 patients will receive only intra-articular injection of 2 ml of placebo followed by 2 ml of hyaluronan. The patients will be followed up for a total of 2 years after IMP administration. The details of the study are found in the Clinical Trials Registry of India (CTRI/2018/09/015785).

#### **Figure 4.**

*ICOAP results. ICOAP: (A, B) total; (C, D) continuous pain; and (E, F) intermittent pain. Data presented as mean value ± SD; C1 = cohort 1; C2 = cohort 2; 25M, 50M, 75M, 150M = 25, 50, 75, 150 million cells, respectively; 1M, 3M, 6M, 12M = 1, 3, 6, 12 months, respectively; ICOAP = Intermittent and Constant Osteoarthritis Pain.*

#### **9. Conclusion**

Osteoarthritis is a common disorder involving damage to synovial joint tissues particularly the cartilage and bone. Current treatments are mostly targeted at end-stage disease, but biological therapies including stem cell therapy show a promise for earlier intervention with a more prolonged benefit. With all the published clinical trial data, it is reasonable to expect that MSCs may prove to be an important therapy for OA. Pooled BMMSCs with their enhanced anti-inflammatory potential, immunomodulatory properties, and secretion of paracrine factors create the optimum environment for a controlled reparative pathway in the affected joint. Pooled BMMSC treatment, perhaps combined with other modalities like a scaffold, would be advantageous in providing treatment in early OA to slow disease progression, thus delaying or avoiding total joint replacement.

#### **Acknowledgements**

We thank Stempeutics Research Pvt. Ltd. and Mr. BN Manohar for proving the required funding for the relevant studies. We would like to thank

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India

**Author details**

Charan Thej and Pawan Kumar Gupta\*

provided the original work is properly cited.

Stempeutics Research Pvt. Ltd., Manipal Hospitals Whitefield Pvt. Ltd., Bengaluru,

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: pawan.gupta@stempeutics.com

*The Role of Mesenchymal Stromal Cells in the Management of Osteoarthritis of the Knee*

Dr. Anish S Majumdar and Dr. Sudha Balasubramanian for their critical scientific inputs for potency assay development, preclinical studies, and clinical studies conducted by Stempeutics Research. We also thank Dr. Anoop Chullikana for his

*DOI: http://dx.doi.org/10.5772/intechopen.86016*

valuable inputs in the clinical studies.

The authors declare no conflict of interests.

**Conflict of interest**

*The Role of Mesenchymal Stromal Cells in the Management of Osteoarthritis of the Knee DOI: http://dx.doi.org/10.5772/intechopen.86016*

Dr. Anish S Majumdar and Dr. Sudha Balasubramanian for their critical scientific inputs for potency assay development, preclinical studies, and clinical studies conducted by Stempeutics Research. We also thank Dr. Anoop Chullikana for his valuable inputs in the clinical studies.
