Monovisc

CLINICAL PHARMACOLOGY

Clinical Studies

Monovisc 0702 Pivotal Clinical Trial

Study Design

The Monovisc 0702 study was a randomized, double-blinded, saline-controlled study conducted under IDE at 31 centers in the U.S. and Canada to evaluate the safety and effectiveness of a single injection of Monovisc™ in patients with symptomatic osteoarthritis of the knee. A total of 369 patients were enrolled. Patients were randomized in a 1:1 ratio to either Monovisc™ or saline injection. The outcome measures collected included the pain and physical function subscales from the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Visual Analog Scale, investigator and patient global assessments and the use of rescue medication. The primary endpoint was to determine the superiority of Monovisc™ compared to saline by evaluating the proportion of patients achieving ≥ 40% relative improvement and ≥ 15mm absolute improvement from baseline in the WOMAC VAS Pain Score (100mm scale) through Week 12.

Study Population

The patients enrolled in the study were between 35 and 75 years old and had the diagnosis of idiopathic OA based upon clinical and/or radiographic criteria of the American College of Rheumatology. Patient exclusion criteria generally included conditions or medications that could confound the assessment of pain and conditions that could be adversely affected by an intra-articular injection. A total of 369 patients were randomized to either Monovisc™ (n=184) or saline (n=185). These 369 patients comprised the Safety Population. The Intent to Treat (ITT) Population included all randomized subjects who received the study injection and had at least one follow-up visit (n=365). The Per-protocol (PP) Population included all randomized subjects who received the study injection, had at least one follow-up visit, and had no major protocol deviations (n=334). Table 1 summarizes the baseline and patient demographic characteristics for the ITT population.

Table 1: Monovisc 0702 Baseline and Patient Demographic Summary

Patient Screening Characteristics All Patients
(N=365)
MONOVISC™
(N=181)
Saline
(N=184)
Age (years)
Mean 59.2 59.7 58.7
Median 60 60 59
Standard Deviation 8.6 7.9 9.2
Gender [N (%)]
Male 152 (41.6%) 74 (40.9%) 78 (42.4%)
Female 213 (58.4%) 107 (59.1%) 106 (57.6%)
Body Mass Index (kg/m^2)
Mean 30.1 29.8 30.4
Median 29.6 29.1 30
Standard Deviation 4.6 4.7 4.6
Kellgren-Lawrence (K-L) Score - Study Knee
Grade II 200 (54.8%) 103 (56.9%) 97 (52.7%)
Grade III 165 (45.2%) 78 (43.1%) 87 (47.3%)
Baseline WOMAC Pain Score – Index Knee (mm)
Mean 293 294 291.5
Median 291 296 288
Standard Deviation 60.3 60 60.7
Baseline WOMAC Pain Score – Contralateral Knee (mm)
Mean 62.5 59.5 65.5
Median 54 44 60
Standard Deviation 48.2 48 48.4

Treatment and Evaluation Schedule

Patients were followed for 26 weeks. Study visits were scheduled for screening, baseline, and weeks 2, 4, 8, 12, 20, and 26. Injections were performed aseptically at the baseline visit. Patients were required to discontinue all analgesics, including NSAIDs, for 7 days prior to the baseline visit and to accept “rescue” acetaminophen (up to a maximum of 4 grams per day) as the only medication for treatment of joint pain during the study. “Rescue” medication was not permitted within 24 hours of any study visit.

Safety Results

Safety analyses were performed on the Safety Population, which was defined as all randomized patients. Regardless of the cause and device relatedness there were 244 (66.1%) patients that experienced adverse events for the total study cohort, where 121 (65.8%) were observed in the Monovisc™ group and 123 (66.5%) were observed in the control group. There were no significant differences between the treatment and control study groups in the frequency or type of observed adverse events.

The adverse events (AEs) most frequently reported ( > 5 % in each group) and not related to the index knee were arthralgia (17.4% in the Monovisc™ group and 14.6% in the saline group); headache (13.0% in the Monovisc™ group and 15.1% in the saline group); back pain (8.7% in the Monovisc™ group and 8.6% in the saline group); pain in extremity (8.2% in the Monovisc™ group and 7.0% in the saline group); and upper respiratory tract infections (6.0% in the Monovisc™ group and 7.6% in the saline group). Adverse events considered related to the treatment are listed in Table 2. Adverse Events were considered typical of viscosupplementation injections in this patient population and were mild or moderate in severity.

Table 2: 0702 Patients with Treatment-Related Adverse Events

AE Type MONOVISC™
N=184
Control (Saline)
N= 185
Any Adverse Event* 13 (7.1%) 10 (5.4%)
Arthralgia 7 (3.8%) 7 (3.8%)
Joint swelling 2 (1.1%) 2 (1.1%)
Joint stiffness 1 (0.5%) 2 (1.1%)
Injection site pain 3 (1.6%) 0 (0.0%)
Joint effusion 1 (0.5%) 0 (0.0%)
Pain in extremity 1 (0.5%) 0 (0.0%)
Synovitis 1 (0.5%) 0 (0.0%)
Contusion 1 (0.5%) 0 (0.0%)
Subcutaneous nodule 1 (0.5%) 0 (0.0%)
Baker's Cyst 1 (0.5%) 0 (0.0%)
* In some cases patients were involved in more than one AE

Effectiveness Results For Monovisc 0702

In the 0702 study, Monovisc™ did not demonstrate superiority over saline for the primary effectiveness endpoint of patients with ≥ 40 % relative improvement from baseline and ≥ 15 mm absolute improvement from baseline in the WOMAC VAS Pain Score through Week 12 (p=0.145).

Monovisc vs. Orthovisc Non-inferiority Analysis

A non-inferiority analysis was performed to support the effectiveness of Monovisc™ for its intended use that compared Monovisc™ with Orthovisc® , which was approved in PMA P030019 for treatment of knee pain due to osteoarthritis. Monovisc™ offers in a single injection the equivalent dose of three injections of Orthovisc® . The effectiveness of Orthovisc® for the treatment of knee pain due to osteoarthritis was demonstrated for either 3 or 4 injections of Orthovisc® using a combined data set from two randomized, controlled, double-blind multicenter IDE studies; OAK9501 and OAK2001. The combined dataset included the following groups listed in Table 3, and included a combined 3-injection Orthovisc® group (O3A1/O3) that consisted of 173 patients (83 patients from the OAK9501 study and 90 patients from the OAK2001 study). The primary non-inferiority analysis compared both the Monovisc 0702 ITT and PP populations to the Orthovisc® 3-injection groups (O3A1, O3, and the combined O3A1/O3 group).

Table 3: Orthovisc® Combined Dataset Treatment Arms

Group Study Description N
O4 OAK2001 Four injections of Orthovisc 104
O3 OAK9501 Three injections of Orthovisc 83
O3A1 OAK2001 Three injections of Orthovisc plus one arthrocentesis 90
O3A1/O3 OAK9501+ OAK2001 Combined group of three injections of Orthovisc 173
A4 OAK2001 Four arthrocentesis procedures (control) 100
Saline OAK9501 Three injections of Saline (control) 81

The non-inferiority margins were set conservatively at Δ5.0mm (on a 100mm WOMAC VAS Scale), or 5% for endpoints expressed as percentages. The mean differences between treatment groups are calculated and a lower one sided 97.5% confidence interval is constructed. If the lower bound is greater than -Δ, then 'Non-inferiority' is obtained for Monovisc™ relative to the three-injection Orthovisc® group. If, in addition, the lower bound of the confidence interval is above zero, the Monovisc™ comparison is determined to be 'Non-inferior and Superior.'

Primary and secondary endpoints for the non-inferiority analysis were the same used for Orthovisc® approval. The primary endpoints were the comparison of the Proportion of Responders at the 20%, 40%, and 50% threshold levels. Secondary endpoints were the change from baseline for the WOMAC Pain Score, Pain on Standing Score, Investigator Global Assessment Score, and Patient Global Assessment Score.

Non-inferiority Analysis Results

The mean Proportions of Responders for the primary endpoints are summarized in Table 4. For all the threshold levels, the Monovisc™ ITT or PP populations have a higher Proportion of Responders as compared to the three-injection Orthovisc® groups.

Table 4: Mean Proportion of Responders from GEE Model (Weeks 7-22)

Variable M1 PP
N=164 %, CI
M1 ITT
N=181 %, CI
O3A1
N= 90 %, CI
O3
N= 83 %, CI
O3A1/O3
N=173 %, CI
O4
N= 104 %, CI
A4
N=100 %, CI
Saline
N= 81 %, CI
20% Improvement in WOMAC 74.2 (67.7, 80.7) 72.4 (65.8,79.1) 63 (52.8, 73.2) 70.8 (60.8, 80.8) 67 (52.8, 81.3) 73.1 (64.4, 81.8) 62.9 (53.7, 72.2) 60.2 (49.3, 71.1)
40% Improvement in WOMAC 61.8 (54.5, 69.0) 58.9 (51.6, 66.2) 50.2 (39.6, 60.7) 54.5 (43.5, 65.4) 52.5 (37.3, 67.7) 63.4 (54.0, 72.9) 48 (38.4, 57.6) 41 (30.1, 52.0)
50% Improvement in WOMAC 53.6 (46.2, 61.0) 51.2 (43.8, 58.6) 43.3 (32.9, 53.8) 46.3 (35.4, 57.3) 45 (29.9, 60.1) 55.6 (45.9, 65.4) 42.6 (33.2, 52.1) 34.4 (23.8, 44.9)

Non-inferiority analyses for all endpoints were conducted using the GEE repeated measures model for weeks 7-22. The Monovisc™ ITT and PP study populations were each compared to the Orthovisc® three-injection groups (O3A1, O3, and the combined effectiveness O3A1/O3 group) for the purposes of establishing non-inferiority. Additional comparisons to the other treatment arms (O4, A4, and Saline) that were used to support the Orthovisc® PMA approval were also made.

The results of the primary endpoint analysis show that Monovisc™ (ITT or PP) is non-inferior to three injections of Orthovisc® for the O3A1 group and also for the combined O3A1/O3 group for all threshold levels. Non-inferiority was not demonstrated against the O3 group with the chosen margin.

The results from the secondary endpoints show that Monovisc™ (ITT or PP) was non-inferior to the three-injection Orthovisc® groups O3 and combined O3A1/O3 for Change in WOMAC Pain Score, Pain on Standing Score, Investigator Global Score, and Patient Global Score. Monovisc™ (ITT or PP) was non-inferior to the O3A1 group for Change in WOMAC Pain Score, Investigator Global Score, and Patient Global Score (PP only).

Monovisc™ was not shown to be non-inferior to four injections of Orthovisc® (O4). The four-injection series of Orthovisc® represents a 33% increase in HA dose compared to a single injection of Monovisc™.

Monovisc™ (ITT or PP) was non-inferior or 'non-inferior and superior' against the control groups A4 and Saline for primary and secondary endpoints.

The clinical significance for the change from baseline for each of the secondary endpoints was demonstrated using Cumulative Distribution Function (CDF) plots comparing the Monovisc 0702 PP Population to the Orthovisc® three-injection combined effectiveness subgroup (O3A1/O3) at each timepoint. Figure 1 shows an example plot for the Change in WOMAC Pain Score at 20-22 weeks. The vertical dashed black line in the plot is set at the “minimum clinically important difference” (MCID). The MCID of 6.0mm was previously determined to be an acceptable difference for HA injectable products based on a meta-analysis of literature.

Figure 1: CDF Plot for Change in WOMAC Pain Score for M1 PP vs. O3A1/O3 (Weeks 20-22)

CDF Plot for Change in WOMAC Pain Score for M1 PP vs. O3A1/O3 - Illustration

The CDF curves for the endpoints (WOMAC Pain Score, Pain on Standing Score, Investigator Global Score and Patient Global Score) show that the Monovisc™ PP population demonstrates a higher degree of clinical improvement at every timepoint relative to the Orthovisc® 3-injection combined effectiveness group (O3A1/O3).

Monovisc 0802 Repeat Injection Extension Study

Study Design and Results:

An open label study, Monovisc 0802, was conducted as an extension study of Monovisc 0702 in order to evaluate the safety of a repeat injection of Monovisc™. The extension study enrolled 240 patients, 119 of whom received a second injection of Monovisc™ and 121 of whom received an injection of Monovisc™ after receiving a saline injection during the initial treatment.

The percentage of patients experiencing AEs, regardless of cause and device relatedness, was similar for those who were previously injected with Monovisc™ (49.6%) and those previously injected with saline (45.5%). The local adverse event profile for the injected knee for those receiving a second injection of Monovisc™ was similar to the adverse event profile seen in the Monovisc 0702 study, regardless of whether patients had initially received a Monovisc™ injection or a saline injection (Table 5).

Table 5: Monovisc 0802 Adverse Events of the Injected Knee Regardless of Relatedness

Adverse Event (per patient) Monovisc after Monovisc initial injection
N=119
Monovisc after Saline initial injection
N=121
Injection site erythema 0 (0.0%) 1 (0.8%)
Injection site edema 2 (1.7%) 3 (2.5%)
Injection site pain 6 (5.0%) 4 (3.3%)
Injection site reaction NOS† 1 (0.8%) 2 (1.7%)
Pain NOS† 1 (0.8%) 1 (0.8%)
Bursitis 1 (0.8%) 0 (0.0%)
Joint effusion 1 (0.8%) 1 (0.8%)
Joint stiffness 1 (0.8%) 1 (0.8%)
Joint swelling 1 (0.8%) 2 (1.7%)
Localized osteoarthritis 2 (1.7%) 1 (0.8%)
†NOS = Not Otherwise Specified

Last reviewed on RxList: 3/21/2014
This monograph has been modified to include the generic and brand name in many instances.

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