For the use of a Registered Medical Practitioner or a Hospital or a Laboratory only

1. GENERIC NAME

Adult human bone marrow-derived, cultured, pooled allogeneic Mesenchymal Stromal Cells (BMMSCs) for Intra-articular injection

2. BRAND NAME

CIPLOSTEM FOR INTRA-ARTICULAR INJECTION

3. BLACK BOX WARNING

None

4. QUALITATIVE AND QUANTITATIVE COMPOSITION

4.1 General Description

CIPLOSTEM is an expanded, cultured, pooled human allogeneic mesenchymal stromal cells extracted from adult human bone marrow.

4.2 Qualitative and Quantitative Composition

Each cryovial contains:

Adult human bone marrow derived cultured pooled Mesenchymal stromal cells……………………25 million/1 mL solution.

The excipient (inactive ingredients) is 1 ml CryoStor® CS5 and 1ml Multiple Electrolyte Solution.

5. DOSAGE FORM AND STRENGTH

CIPLOSTEM is a formulation of adult human bone marrow-derived, cultured, pooled allogeneic mesenchymal stromal cells (BMMSCs) intended for intra-articular injection only. CIPLOSTEM is provided as a frozen cell suspension in a cryovial containing 25 million MSCs per 1 ml. After thawing it has to be reconstituted using 1 ml of Multiple Electrolyte Solution. The total volume of the suspension before administration is 2 ml.

6. CLINICAL PARTICULARS

6.1 Therapeutic Indication

Grade II and Grade III Osteoarthritis of knee based on Kellgren and Lawrence radiographic criteria in non – obese patients with BMI <30kg/m².

6.2 Posology and Method of Administration

Recommended Dose and Dosage Adjustment

Pre-treatment

It is recommended to administer premedication of appropriate dosage of IV steroid (e.g., 100mg of hydrocortisone) and antihistaminic (e.g., 45.5mg pheniramine maleate) within 60 minutes prior to injection of CIPLOSTEM. This is to prevent any potential hypersensitivity reaction after administration of CIPLOSTEM, which is characterized by fever, chills, rash and hypotension. However, till now, there has not been any report of hypersensitivity reaction in clinical trials conducted using CIPLOSTEM.

Dose

Single intra-articular dose of 25 million cells suspended in 1 ml CryoStor CS5^® + 1 ml PlasmaLyte A followed by 2 ml Sodium Hyaluronate injection.

Administration

CIPLOSTEM will be administered intra-articularly, using 5 ml syringe, preferably under ultrasound guidance under all aseptic precautions. The intra-articular injection will be performed by qualified doctor using a 2.0 inch (5.1 cm) 20G needle mostly as a medial or lateral para-patellar injection (an injection into the patello-femoral joint) but optimal joint positioning and site of needle insertion for the affected knee may vary according to the anatomic and pathologic conditions present.

After injecting CIPLOSTEM, the syringe will be detached from the 20G needle (which is not removed from the site of injection) and injection Hyaluronic acid which is a pre-filled syringe, (molecular weight 500,000 – 730,000 Daltons) will be administered through the same needle. Hence piercing of the needle intra-articularly will be done only once.

Reconstitution Procedure

The CIPLOSTEM reconstitution will be done as a single step procedure, where the Crystal Zenith (CZ) cryovial containing 25 million MSCs in 1 ml of Cryostor^® CS5 will be thawed in a pre-heated water bath at temperature of 37 ± 1⁰C and 1 ml of Multiple Electrolyte Solution will be injected into the CZ cryovial to make a total volume of 2 ml. The entire volume of CIPLOSTEM is aspirated from the vial into the 5 ml syringe and injected to the patient.

Cryobox containing the cryovials of CIPLOSTEM is taken out from dry shipper using cryogloves. Remove CZ vial containing CIPLOSTEM from the cryobox and hold the seal of the CZ vial and slowly dip up to neck region and swirl the CZ vial in the water bath which is pre-heated at 37 ± 1⁰C for 3-4 minutes to thaw the vial. Aseptically aspirate 1 ml of Multiple Electrolyte Solution, with the 2 ml sterile syringe and 18G needle and add the aspirated 1 ml Multiple Electrolyte Solution into the vial by inserting the 18G needle attached to the 2 ml syringe into the rubber stopper that is visible in the centre of the aluminium seal. Mix the Multiple Electrolyte Solution and the cell suspension uniformly. Avoid air bubbles. Now the 2 ml suspension of cryovial contains 25 million cells in 1 ml Cryostor^® CS5 + 1ml Multiple Electrolyte Solution. Thus, the final suspension in the vials contains 25 million cells per 2 ml.

Method of Administration

Shake gently before use.
Do not add any other medicines to the contents.
Administer through disposable sterile syringes.
Use within 60 minutes after reconstitution.
CIPLOSTEM will be administered intra-articularly, using 5 ml syringe, preferably under ultrasound guidance under all aseptic precautions.
The intra-articular injection will be performed by qualified doctor using a 2.0 inch (5.1 cm) 20G needle mostly as a medial or lateral para-patellar injection (an injection into the patello-femoral joint) but optimal joint positioning and site of needle insertion for the affected knee may vary according to the anatomic and pathologic conditions present.
After injecting CIPLOSTEM, the syringe will be detached from the 20G needle (which is not removed from the site of injection) and injection Hyaluronic acid which is a pre-filled syringe, (molecular weight 500,000 – 730,000 Daltons) will be administered through the same needle. Hence piercing of the needle intra-articularly will be done only once.

6.3 Contraindications

History of Bleeding disorders
Known hypersensitivity to Hyaluronic acid products or animal sera or constituents of CIPLOSTEM.

6.4 Special Warnings and Precautions for Use

The intra-articular injection CIPLOSTEM should be injected immediately after preparing the suspension and it should not be stored.
Injection of CIPLOSTEM should not be carried out if the CZ vial was kept in the dry shipper beyond the Use before date or if the temperature logger displays temperature above -185°C when the CZ vial is being retrieved from the dry shipper.
Injection of the CIPLOSTEM should not be carried out if the CZ vial is found to be damaged or leaking.

Risk of Transmission of Infectious Agents

CIPLOSTEM is a pooled product from healthy volunteer bone marrow donors. The possibility of transmission of infectious agents cannot be completely excluded as with any blood or marrow derived product. Stempeutics Research has taken specific measures to reduce this potential risk as outlined below:

Rigorous donor screening, including physical exam and medical history
Donor testing for infectious diseases including Human Immunodeficiency Virus (HIV)-1 and II, hepatitis B and hepatitis C viruses, Human T Lymphotropic Virus (HTLV), Syphilis, Cytomegalovirus (CMV), Epstein-Barr Virus (EBV) and Parvovirus B-19. Certain of these tests are repeated during manufacturing.
Use of reagents in manufacture that are sterile and have undergone viral inactivation, where appropriate. Bovine serum used in the manufacturing process is carefully sourced from Transmissible Spongiform Encephalopathy (TSEs) and Bovine Spongiform Encephalopathy (BSE) free countries to minimize the risk of TSE-BSE infectivity.
During the manufacturing process, testing for viral and adventitious agents is performed, including sterility, endotoxin and mycoplasma testing.
At the end of processing, final testing for viral and adventitious agents is performed, including sterility, endotoxin and mycoplasma.
All the testing must be negative before the product can be released for use.

Risk of Hypersensitivity

Patients with known hypersensitivity to Hyaluronic acid products or animal sera or constituents of CIPLOSTEM might develop hypersensitivity reaction characterized by fever, chills, rash and hypotension.

To reduce this potential risk of hypersensitivity, patients should be monitored for signs and symptoms of hypersensitivity reaction while on treatment with CIPLOSTEM.

Caution should also be used when administering CIPLOSTEM to patients with a known sensitivity to porcine (pig) or bovine (cow) products, because trace amounts of these components used in manufacturing may be present in the final product.

Risk of Administration Site Pain/ Swelling

The patient might develop injection site joint pain, joint swelling and injection site joint effusion. The probable mechanism is injection site procedure/technique or by stem cell injection itself

It is recommended to monitor the signs and symptoms of administration site pain or swelling when CIPLOSTEM is administered. Intra-articular injection, using 5 ml syringe, under all aseptic precautions into the knee joint should be performed preferably under ultrasound guidance.

6.5 Drug Interactions

This medicinal product must not be mixed with other medicinal products.

Drug-Laboratory Interactions

There is no evidence from preclinical or clinical studies that CIPLOSTEM has a direct effect on laboratory test

Drug-Drug Interactions

No specific drug interaction studies have been conducted with CIPLOSTEM. No clinically relevant drug interactions have been reported when CIPLOSTEM was administered with analgesics in clinical trials.

The effects of lifestyle choices such as smoking and alcohol consumption on CIPLOSTEM have not been established.

Drug-Food Interactions

There have not been any reports of food interactions with CIPLOSTEM. BMMSCs are naturally occurring cells in the body and would not be expected to have any interactions with food.

6.6 Use in Special Populations:

Patients with Hepatic or Renal Impairment

Data on the use of CIPLOSTEM in patients with hepatic or renal impairment is not available, however, given the cell – based nature of CIPLOSTEM and being locally administered by intra-articular route it is not expected that the benefit – risk profile of CIPLOSTEM in patients with hepatic or renal impairment will differ from that observed in patients with normal hepatic or renal function. Therefore, no dose adjustment is required in hepatic or renal impairment.

Pregnant Women

Pregnant women have been excluded from CIPLOSTEM clinical trials, therefore guidance on treating these patients cannot be provided.

Lactating Women

Lactating women have been excluded from CIPLOSTEM clinical trials, therefore guidance on treating these patients cannot be provided.

Geriatric Patients (above 65 years)

Data on use of CIPLOSTEM in the elderly population are limited, however, given the cell – based nature of CIPLOSTEM and its local administration by intra-articular route, it is not expected that the benefit – risk profile of CIPLOSTEM will differ from that observed in non – elderly patients. Therefore, no dose adjustment is required in elderly patients.

Paediatric Patients (below 18 years)

Paediatric patients have been excluded from CIPLOSTEM clinical trials, therefore guidance on treating these patients cannot be provided.

Ethnicity

CIPLOSTEM has been tried in Indian ethnic population and no data exists of being injected in different ethnic groups. Seeing the safety profile of MSCs it is expected that the safety profile of CIPLOSTEMwill not differ in different ethnic populations.

6.7 Effects on Ability to Drive and Use Machinery

There is no data that CIPLOSTEM is safe or unlikely to produce an effect on the ability to drive or use machinery immediately after its administration.

6.8 Undesirable Effects

Adverse Effects

The adverse events observed in clinical trials evaluating CIPLOSTEM in osteoarthritis have been primarily the manifestations of the underlying disease. Common adverse events seen in clinical trials are: injection site joint pain, injection site joint swelling, injection site joint effusion and documented hypersensitivity to administered drug. The treatment given for these adverse effects includes but not limited to analgesic and cold fomentation.

6.9 Overdose

Overdose has not been reported in clinical trials till date and the maximum tolerated dose of CIPLOSTEM has not been established in humans. Doses up to 150 million BMMSC’s have been administered to patients in clinical trials without dose-limiting toxicity.

7.0 PHARMACOLOGICAL PROPERTIES

7.1 Mechanism of Action

Osteoarthritis (OA) is associated with damage to the articular cartilage. Conversely, any cartilage injury ultimately leads to OA due to the lack of reparative processes.

BMMSCs have anti-inflammatory and immunosuppressive properties which reduce inflammation in the knee joint. BMMSCs may initiate the repair process by differentiating into chondrocytes or by inducing proliferation and differentiation of existing chondro-progenitors into mature chondrocytes or both. BMMSCs express a host of transcription factors, biological modulators and extracellular matrix proteins which may play a pivotal role in enhancing neo-cartilage formation. The various factors implicated for cartilage tissue synthesis are bone morphogenic protein (BMP), fibroblast growth factor, glioblastoma transcription factor 1, homeobox protein A, insulin-like growth factor 1 (IGF-1), interleukin, parathyroid hormone-related protein, Runt related transcription factor 2, sex determining region Y-box 9 gene, signal transducers and activators of transcription factor 1 and transforming growth factor-beta (TGF-β). BMMSCs influence the local osteoarthritic microenvironment by stimulating resident chondrogenic progenitor cells (CPC) and promote their differentiation into mature chondrocytes mediated by secretion of bone morphogenetic proteins (BMPs) and TGFβ1. BMMSCs are known to differentiate into chondrocytes in vitro using differentiation cues such as BMP-7 and TGFβ1. A similar mechanism could be involved in the differentiation of BMMSCs in vivo. With the increase in the levels of BMP-7 and TGFβ1 in the local joint milieu, mediated by a change in expression of master regulatory genes such as Sox9, HoxA, HoxD, and Gli3, BMMSCs could differentiate into chondrogenic progenitor cells (CPCs) in vivo. The CPCs further differentiate into chondroblasts characterized by definitive upregulation of collagen types II B, IX, and XI. Subsequently, the CPCs differentiate into mature chondrocytes regulated by balanced expression of collagen X (Col X) and synthesize the secretion of collagen II which is made of sGAG building blocks which maintain the structural integrity of hyaline cartilage. Very high expression of collagen X has been linked to hypertrophy of chondrocytes and formation of fibrous cartilage, and thus a regulated expression of Col X would likely result in deposition of hyaline cartilage. From the above-described multimodal mechanism of action (MoA), it is clear that BMMSCs are an ideal cell population which could contribute significantly for an effective treatment of OA.

7.2 Pharmacodynamic Properties

Pharmacodynamic Interactions

CIPLOSTEM has anti-inflammatory and immunosuppressive properties which reduce inflammation in the knee joint. It initiates the repair process by differentiating into chondrocytes or by inducing proliferation and differentiation of existing chondro-progenitors into mature chondrocytes or both. CIPLOSTEMexpresses a host of transcription factors, biological modulators and extracellular matrix proteins which may play a pivotal role in enhancing neo-cartilage formation. The various factors implicated for cartilage tissue synthesis are bone morphogenic protein (BMP), fibroblast growth factor, glioblastoma transcription factor 1, homeobox protein A, insulin-like growth factor 1 (IGF-1), interleukin, parathyroid hormone-related protein, Runt related transcription factor 2, sex determining region Y-box 9 gene, signal transducers and activators of transcription factor 1 and TGF-β. Preclinical efficacy of CIPLOSTEMhas been demonstrated on MIA (monosodium iodoacetate) ‑induced OA in Wistar rats. The study outcomes were evaluated based on the pressure application measurement (PAM) score, morphological and histological evaluation of the cartilage. The study demonstrated the efficacy of CIPLOSTEM in knee OA for both high and low doses in significant pain recovery, improved macroscopic and histologic grading scores in animals compared to the ones injected with either Hyaluronic acid (HA) or vehicle only.

7.3 Pharmacokinetic Properties

The biodistribution kinetics of CIPLOSTEM was studied using Immunofluorescence staining for human nuclear antigen (HNA) using a MIA induced OA animal model. The staining was done was carried out to trace the survival and migration pattern of the BMMSCs in the knee joints. The HNA labelled cells were found throughout the osteoarthritic cartilage at 4 weeks post cell transplantation. The labelled cells gradually disappeared from the cartilage at 8 and 12 weeks post transplantation.

8.0 NON-CLINICAL PROPERTIES

8.1 Animal Toxicology and Pharmacology

Single dose acute and sub-chronic toxicity studies were done in rodent and non –rodents animals and they were followed for two weeks and three months respectively after administration of CIPLOSTEM. No Observed Adverse Effect Level (NOAEL) was observed with CIPLOSTEMin dose upto 10 times the therapeutic dose (20 million cells / kg body weight). It was also found to non – genotoxic, non – teratogenic and showed no immunological reactions.

Tumorigenicity study was performed in Severe Combined Immunodeficiency (SCID) mice divided using CIPLOSTEM by subcutaneous (SC) and intramuscular (IM) injections and the animals were followed up for 6 months. There was no evidence of tumor formation attributed to CIPLOSTEM. In addition, there has been no evidence of tumor or ectopic tissue formation in long-term subchronic toxicity studies (up to 3 months) in rat and rabbit model. No cases of ectopic tissue formation were reported due to CIPLOSTEM administration in clinical studies.

In a pre-clinical efficacy study, 80 healthy male Wistar rats were selected and were divided into five treatment groups. In these animals, OA was induced by injecting MIA intra-articularly. The effect of MSC on Monoiodoacetate (MIA) induced OA in rats was evaluated by pain hypersensitivity using PAM score, morphological examination and histopathological investigation of knee joint cartilage, and expression of cartilage-specific proteins and proteoglycans. For histopathological studies, a predetermined number of animals were sacrificed at 4, 8, and 12 weeks after cell injection. At the same time point, a certain number of animals belonging to other treatment groups were also sacrificed for comparison.

Results demonstrated that during the experimental period, weekly body weight data showed normal growth pattern in saline-injected normal control animals and all the MIA-injected experimental group animals that were treated with PlamaLyte-A (PLA), HA and high and low doses of CIPLOSTEM. No statistically significant difference was observed in body weight of treatment groups when compared to MIA + PLA injected group. Similarly, no difference was seen in feed consumption pattern in all the groups throughout the experimental period.

The PAM score were recorded weekly once throughout the study period. Scores demonstrated an increase in pain threshold in both the cell treated groups (high and low dose groups) as compared to the HA group till the end of the study. This increase was found to be statistically significant up to 8 weeks of treatment. The mean PAM score after 8 weeks follow-up for the HA treated group was 540 g F as compared to the PAM score recorded for the CIPLOSTEM high dose group which was 716 g F (p<0.001), and for the CIPLOSTEM low dose group which was 666 g F (p<0.01). In terms of pain recovery, both the BMMSC treated groups recorded increased pain recovery from week 3 onwards as compared to the HA treated group, and this recovery was maintained till the end of the study period (from 8.8% to 36.6% at the end of 12 weeks).

The flow cytometric method was used at various time points to check the immunosuppression. Treatment with either dose of CIPLOSTEM caused maximum reduction in CD4 count at the tested time points when compared to Saline + PLA group.

Macroscopic examination of the knee joints to assess cartilage lesions demonstrated that 86.7% of MIA + PLA injected animals were osteoarthritic. Treatment with HA showed 46.7% of the animals with less cartilage damage; whereas high dose of CIPLOSTEM resulted in 73.3% and low dose resulted in 60% protection from cartilage damage, respectively. The histological sections of the femoral cartilage were scored by OARSI grading (Osteoarthritis Research Society International) to assess the severity of disease pathology. A significant reduction in the OARSI grade (3.61 to 1.61) was observed in both the CIPLOSTEM treated groups at weeks 8 and 12 as compared to the HA group. Based on the gross and histological assessment, there was a significant prevention of cartilage damage by CIPLOSTEM in a dose dependent manner indicating the active contribution of CIPLOSTEM in modulating the OA disease progression.

Safranin-O stained sections of 4^th, 8^th and 12^th week showed good correlation with the histological features seen in hematoxylin andeosin slides. Thus, the sections with extensive cartilage damage showed loss of Safranin-O staining along the articular cartilage. CIPLOSTEM injected knee joint sections were found to retain Safranin-O staining in all the termination points; hence this indicates prevention of cartilage damage and probable role of CIPLOSTEM treatment in cartilage regeneration. Immunofluorescence staining for human nuclear antigen (HNA) was carried out to trace the survival and migration pattern of the CIPLOSTEM in the knee joints. The HNA labeled cells were found throughout the OA cartilage at 4 weeks post cell transplantation. The labeled cells gradually disappeared from the cartilage at 8 and 12 weeks post transplantation.

To conclude, OA was successfully induced in male Wistar rats by injecting MIA intra-articularly. The human CIPLOSTEM treatment was found to be efficacious for treating OA induced by MIA in animal models. Both high and low doses of CIPLOSTEM along with HA demonstrated significant pain recovery, improved macroscopic and histological grading scores in animals compared to the ones injected with either HA or vehicle only. No significant loss in body weight was observed in animals treated with PLA, HA and low and high dose of CIPLOSTEM which reveals that there was no systemic toxicity upon treatment. These results collectively suggest that intra-articular injection of CIPLOSTEM with HA is potentially beneficial for the treatment of OA.

9.0 CLINICAL PROPERTIES

OA is a chronic multifactorial disease characterized by progressive joint degeneration accompanied by subchondral bone sclerosis which can lead to the formation of bone cysts and marginal osteophytes. Early in the disease, joints may ache after physical work or exercise. Most often, OA occurs in the hands, hips, knees, neck or low back.

Treatment of OA aims at reducing pain, maintaining mobility, and minimizing disability. They are generally classified as pharmacologic, non-pharmacologic, surgical, and complementary and/or alternative, typically used in combination to achieve optimal results.

General measures taken to treat OA are by exercise, weight control, using a knee brace, and physiotherapy and NSAIDs (Non-steroidal anti-inflammatory drugs). NSAIDs can cause gastritis, tinnitus, cardiovascular problems, bleeding problems and liver and kidney damage. Older people have the highest risk of complications. Although intra or peri-articular injection of a glucocorticoid preparation may provide marked symptomatic relief for weeks to months, studies in animal models have suggested that glucocorticoids may produce cartilage damage and frequent injections of large amounts of steroids have been associated with joint breakdown in humans.

As per the AAOS (American Association of Orthopaedic Surgeons) recommendations, intra-articular injection of sodium Hyaluronic acid has been approved for treatment of patients with OA of the knee but still there is ambiguity about its efficacy as no difference in efficacy was observed in lower molecular strength of Hyaluronic acid formulation and placebo. None of these approaches can actually cause significant regeneration of the damaged cartilage.

CIPLOSTEM has anti-inflammatory and immunosuppressive properties which reduce inflammation in the knee joint. CIPLOSTEM may initiate the repair process by differentiating into chondrocytes or by inducing proliferation and differentiation of existing chondro-progenitors into mature chondrocytes or both.

Two separate CDSCO approved clinical trials (Phase II and Phase III) were conducted in Knee OA patients to determine the safety and efficacy of CIPLOSTEM administration via intra-articular route.

Phase II Study

In the Phase II study conducted in India, 60 subjects were recruited and randomized in a 2:1 ratio to receive either CIPLOSTEM or placebo (PLA). Of these, 40 subjects received CIPLOSTEM and 20 subjects received PLA. Thus at each dose level, 10 subjects received CIPLOSTEM and 5 subjects received placebo. All the 60 patients completed the 2-year follow up in this study and the data is summarized below.

Subjects who received D25M, 50 million MSCs were considered as Cohort 1, and subjects who received D75M and 150 million MSCs were considered as Cohort 2. Subjects who received 2 ml placebo (2 ml PlasmaLyte A) were considered as group P1 and who received 4 ml placebo (4 ml PlasmaLyte A) was considered as group P2. Subjects who were randomized to groups D25M, D50M and P1 were considered as cohort 1, and patients who were randomized to groups D75M, D150M and P2 were considered as cohort 2.

The results of the phase II study conducted suggest that CIPLOSTEM is safe in the studied patient population, which was the primary endpoint of the trial. Most of the treatment emergent adverse events (TEAEs) were mild to moderate in severity and assessed as unrelated to the Investigational Medicinal Product (IMP). The TEAEs injection site joint pain, injection site joint swelling, documented hypersensitivity to administered drug were assessed as definitely related to CIPLOSTEM .The TEAE respiratory tract infection (was assessed as probably related to CIPLOSTEM. Six serious adverse events (SAEs) were reported during the course of the study. One SAE - Injection site joint effusion was assessed as possibly related by the investigator. The other 5 SAE‘s were assessed as unrelated or remotely related. All SAEs resolved during the study. No major laboratory abnormality was detected in the subjects receiving CIPLOSTEM or in the placebo group.

In summary, the safety results demonstrate that CIPLOSTEM had a favourable safety profile when injected intra-articularly for OA of knee. Complications related to the treatment like injection site reactions and hypersensitivity to study drug was more prevalent in the D75M dose group and D150M dose group.

The efficacy analysis were performed and summarized for the Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain index, stiffness index, physical function, composite index, Intermittent and Constant Osteoarthritis Pain (ICOAP) overall, intermittent pain, constant pain and predictability of pain, OA-pain visual analogue scale (VAS), reduction in intake of analgesics, radiograph of knee, Whole-Organ Magnetic Resonance Imaging Score (WORMS) scoring system (overall, cartilage signal and morphology, sub-articular bone marrow abnormality, sub-articular cysts, sub-articular bone attrition and osteophytes) and cartilage thickness. For all the efficacy parameters, the baseline values, post baseline values and respective change from baseline values at each relevant visit were summarized. The analysis results were compared within each cohort (cohort 1: D25M, D50M and P1 groups, cohort 2: D75M, D150M and P2 groups).

The efficacy results of the study showed that the improvement in subjective parameters were seen in a pronounced manner in 25 million dose group when compared to other groups; however, this difference was not statistically significant.

Phase III Study

The phase III trial is a randomized, double blind, multicentre, placebo controlled assessing the efficacy and safety of intra-articular administration of CIPLOSTEM (adult human bone marrow derived, cultured, pooled, allogeneic mesenchymal stromal cells) in patients with OA of knee joint. A total of 73 patients received CIPLOSTEM (25 million cells) in 1 ml CryoStor^® CS5 + 1 ml PlasmaLyte A followed by 2 mL Hyaluronic acid. The current study report is based on two years follow up of all patients.

In summary, the efficacy data showed there was a significant improvement in patient reported outcomes like WOMAC & VAS scores in CIPLOSTEM group. The primary end point of the study - WOMAC composite index score were significant at one year and two year follow-up (p-value<0.0001) in CIPLOSTEM group as compared to placebo group. Similar results were seen in the WOMAC sub scores (pain, stiffness & physical function) and VAS score, which were significant at one year and two year follow-up (p-value<0.0001) in CIPLOSTEM group as compared to the placebo group.

T2 mapping done by MRI to see the quality of cartilage (hydration & collagen matrix) showed that in medial femorotibial (FT) compartment, superficial cartilage quality of cartilage improved in the CIPLOSTEM group (decrease in T2 relaxation time at Day 730 as compared to baseline) whereas no change in cartilage quality seen in the placebo group (T2 relaxation time > 40ms at every time point). Further, there was no worsening of the deep cartilage in the medial compartment of the knee in CIPLOSTEM group (T2 relaxation time < 40 ms at all time points and decreased from baseline) as compared to placebo group (T2 relaxation time increased to 47ms at Day 365). The average cartilage score in the medial FT compartment shows that the mean values in placebo group increased from 41.0 ms at baseline to > 40 ms at Day 365 and Day 730 (change from baseline was significant; p value <0.0001), whereas all the mean values were within normal range (2.1 to 40 ms) in CIPLOSTEM group at Day 365 and Day 730 (change from baseline not significant). Hence, there was significant deterioration of cartilage quality in placebo group whereas the cartilage quality was maintained in the CIPLOSTEM group. There was an increase in average cartilage total volume of 49.81 units in CIPLOSTEM group as compared to placebo group irrespective of time which was statistically non-significant.

Biomarkers analysis showed that IL-10 values (anti – inflammatory marker) increased by 0.051 pg/mol in CIPLOSTEM group and decreased by -0.228 pg/mol in placebo group at Day 365 (mean difference 0.27 pg/mol), which was non-significant. Similarly, at Day 730, there was an increase by 0.751 pg/mol in CIPLOSTEM group and decrease by -0.601 pg/mol in placebo group (mean difference 1.35 pg/mol), which was non-significant. Further in CIPLOSTEM group there was a decrease in CTX II levels (a measure of C-terminal crosslinked telopeptide type II collagen secreted into urine and indicative of disease progression) of 7.79 ng/mmol and -0.04 ng/mmol at Day 365 and Day 730 respectively as compared to placebo group irrespective of time which was statistically non-significant.

The safety results demonstrate that CIPLOSTEM (adult human bone marrow derived, cultured, pooled, allogeneic mesenchymal stromal cells) continue to have a favorable safety profile when injected intra-articularly for OA of the knee. Few AEs were expected in the CIPLOSTEM group like injection site joint pain, injection site joint swelling, injection site pain and injection site swelling when compared to the placebo group.

Based on the above findings, it can be concluded that CIPLOSTEM is safe and effective in treating KL Grade II and Grade III Osteoarthritis of knee.

10.0 DESCRIPTION

CIPLOSTEM is classified as a Cell or Stem Cell-derived product.

CIPLOSTEM is expanded, cultured, and pooled human allogeneic mesenchymal stromal cells extracted from adult human bone marrow. Each unit/cryovial contains a frozen cell suspension of 25 million cells in 1 ml of Cryostor^® CS5 solution, intended for intra-articular injection only. The excipients (inactive ingredients) are CryoStor^® CS5 and Multiple Electrolyte Solution.

CIPLOSTEM is intended to be administered intra-articularly to patients with the Grade II and Grade III Osteoarthritis of knee based on Kellgren and Lawrence radiographic criteria in non-obese patients with BMI<30kg/m².

11.0 PHARMACEUTICAL PARTICULARS

11.1 List of Excipients

CryoStor^® CS5 (1ml) and Multiple Electrolyte Solution (1ml)

11.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products.

11.3 Shelf-life

CIPLOSTEM has an established shelf-life of 18 months for 25 million cells composition from the date of manufacturing. The reconstituted product should be used immediately from thaw.

11.4 Packaging Information

CIPLOSTEM contains 25 Million BMMSCs in 1 ml of CryoStor^® CS5 suspension.

CIPLOSTEM is packed CZ vials made up of Cyclic Olefin Polymer and have excellent barrier properties and transparency qualities which are comparable to those of glass. The CZ vials is used as a container for this cryopreserved drug product, as it provides safe containment and also offers higher break resistance than glass during transport, storage and end-user handling.

Parts of the CZ vial Closure system:

5 ml CZ vial
Rubber Stopper
Aluminium Seal
Flip off

11.5 Storage and Handling Instructions

Personnel receiving the cryoshipper containing CIPLOSTEM shall ensure the following, prior to product usage:

The CZ vial in the cryoshipper should be used within ‘Use Before’ date mentioned in the label of the dry shipper. If not used, the shipment to be returned to Stempeutics Research Private Limited. Appropriate documentation is received along with the consignment and is as per the requirement.
Cryoshipper is received in sealed and good condition, there is no external visible damage to the cryoshipper, data logger is attached and temperature display is within -185 to -196°C.
Store CIPLOSTEM at -185 to -196°C in vapour phase of liquid nitrogen for long term storage at site or proceed for usage if it is planned to use immediately.

12. PATIENT COUNSELLING INFORMATION

CIPLOSTEM: 25 million Allogenic adult human Bone marrow-derived Mesenchymal Stromal cells (BMMSCs) in 1 ml of suspension for injection

12.1. This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side-effects you may get. See the section 10.3.4. for reporting of side effects.

12.2. Read this entire leaflet carefully before you are given this medicine because it contains important information for you.

Keep this leaflet. You may need to read it again.
If you have any further questions, ask your doctor or surgeon.
If you get any side effects, talk to your surgeon or doctor. This includes any possible side effects not listed in this leaflet. See section 10.3.4.

12.3. What is in this Leaflet?

12.3.1 What is CIPLOSTEM and what is it used for?

12.3.2 What do you need to know before you are given CIPLOSTEM?

12.3.3 How is CIPLOSTEM given?

12.3.4 Possible side effects

12.3.5 How to store CIPLOSTEM?

12.3.6 How do CIPLOSTEM look like and Contents of the pack?

12.3.1. What is CIPLOSTEM and What is it Used for?

CIPLOSTEM is a medicine used for the treatment of osteoarthritis of knee joint. Osteoarthritis is a type of joint disease that results from breakdown of joint cartilage and underlying bone. The most common symptoms are joint pain and stiffness. Usually the symptoms progress slowly over years. Initially they may occur only after exercise but can become constant over time. Other symptoms may include joint swelling, decreased range of motion.

CIPLOSTEM is administered into the joint space of the knee. CIPLOSTEM helps in reducing the inflammation in the knee joint which in turn helps in decreasing the pain in the joint and also increase in quality of life. It also helps in initiating the repair process in the knee joint by differentiating into cells responsible for cartilage formation. It also releases proteins (cytokines) that slow down cartilage deterioration and/or decrease pain.

The active ingredient of CIPLOSTEM is mesenchymal stromal cells which are taken from the bone marrow of a healthy voluntary donor (so called allogeneic stem cells) and then expanded in the laboratory. Adult stem cells are a special type of cells found in many adult tissues, whose primary role is the repair of the tissue in which they are found.

12.3.2. What do you need to know before you are given CIPLOSTEM?

You Must not be Given CIPLOSTEM

If you are allergic to Hyaluronic acid products or animal sera or any of the ingredients of this medicine

Warnings and Precautions

Talk to your doctor or surgeon before you are given CIPLOSTEM
CIPLOSTEM is a living cell therapy and therefore, the final product cannot be sterilised. The product is checked at different stages during its manufacture to ensure that it is free of infection. It is also checked for sterility before it is released, and if it is free of infection, the product is released for use in patients. If after the procedure you feel ill or have fever, inform your physician or surgeon as soon as you can.

12.3.3. How is CIPLOSTEM Given?

You may have had an initial discussion with the doctor or surgeon prior to CIPLOSTEM administration. The following information is related to the day when CIPLOSTEM is administered.

CIPLOSTEM is injected by Orthopaedic surgeon / Rheumatologist into the joint space of the affected knee joint. The recommended dose is 25 million cells.

On the day of injection of CIPLOSTEM, along with physical examination, pulse, blood pressure, respiratory rate and body temperature will be recorded. A pre-medication of 100 mg of intravenous hydrocortisone injection and 45.5 mg intravenous or intramuscular pheniramine maleate injection will be administered within one hour prior to injection of the CIPLOSTEM. CIPLOSTEM will then be injected as intra-articular injection preferably under ultrasound guidance using a 2.0 inch (5.1 cm) 20G needle mostly as a medial or lateral para-patellar injection (an injection into the patello-femoral joint) but optimal joint positioning and site of needle insertion for the affected knee may vary according to the anatomic and pathologic conditions present.

If you have any further questions on the use of this medicine, ask your doctor or surgeon.

12.3.4. Possible Side Effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Injection site joint pain, injection site joint swelling, injection site joint effusion and documented hypersensitivity to administered drug may be observed after the administration of the CIPLOSTEM.

Reporting of side effects

If you get any side effects, talk to your doctor, or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly to:

Pharmacovigilance Programme of India (PvPI)

National Coordination Centre,

Indian Pharmacopoeia Commission,

Ministry of Health & Family Welfare,

Govt. of India, Sector‐23, Rajnagar,

Ghaziabad‐201002.UttarPradesh

Tel.:0120‐2783400, 2783401, 2783392

FAX: 0120‐2783311

Email: pvpi.ipc@gmail.com

Cipla Ltd.

Cipla Ltd.

Cipla House, Peninsula Business Park,

Ganpatrao Kadam Marg, Lower Parel,

Mumbai-400013, India

OR

Email: drugsafety@cipla.com

Toll Free number: 1800-180-3024 (9 am to 5.30 pm weekdays).

Toll-Free Number: 1800-26-77-779

By reporting side affects you can help provide more information on the safety of this medicine. This includes any possible side effects not listed in this leaflet.

12.3.5. How to store CIPLOSTEM?

As this medicine will be used in the hospital, this medicine is directly supplied to the treating hospital / physician. The hospital staff is responsible for correct storage of the medicine before and during its use, as well as for its correct disposal.

12.3.6. What CIPLOSTEM look like and content of the pack?

CIPLOSTEM is a cell suspension containing 25 million MSCs in 1 ml of CryoStor^®CS5 for injection. The cells are supplied in frozen condition in a cryovial and shipped in a cryoshipper at a temperature between -186⁰C to -195⁰ C.

Before injection, the cryovial has to be thawed and mixed with 1 ml of Multiple Electrolyte Solution to make a final volume of 2 ml.

13.0 OTHER INFORMATION

13.1 Use in Children and Adolescents

Do not give this medicine to children and adolescents (i.e. aged under 18 years) because the potential benefits and risks are unknown.

13.2 Use in Pregnancy and Breast-feeding

If you are pregnant or breast-feeding or think you may be pregnant or are planning to have a baby, ask your doctor/surgeon for advice before you are given this medicine. Treatment with CIPLOSTEM is not recommended during pregnancy or while breast-feeding. Women of childbearing age should use effective contraception during treatment with CIPLOSTEM.

13.3 Driving and Using Machines

CIPLOSTEM is not likely to affect your ability to drive or use tools or machines.

13.4 Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

14.0 DETAILS OF MANUFACTURER

Mfd. by Stempeutics Research Pvt. Ltd.

At, 34^th KM, Tumakuru Road,

T-Begur, Nelamangala Taluk,

Bengaluru-562123

15.0 MARKETED BY:

Cipla Ltd.

Registered Office: Cipla House, Peninsula Business Park,

Ganpatrao Kadam Marg, Lower Parel,

Mumbai-400 013, India

16.0 DETAILS OF PERMISSION OR LICENSE NUMBER WITH DATE

Permission No. MF-01/2022; Dated 01 Feb 2023
Amendment dated 20 Jul 2023
Amendment dated 22 Aug 2023
Amendment dated 31 Jan 2024

17. DATE OF ISSUE

27^th May 2025

CIPLOSTEM for Intra-articular Injection