Clinical Pharmacology for Gel-One
Clinical Study
Study Design
The safety and effectiveness of a single injection ofGel-One® for the treatment of symptomatic osteoarthritis of the knee werestudied in a prospective, randomized and double-blind controlled studyconducted at 25 centers in the United States. The safety and effectiveness of asingle injection of Gel-One® was confirmed by protocol SI-6606/01.
A total of 379 patients were randomized at a 2:1 ratio ofGel-One® (n=251) to PBS (n=128); both investigators and patients were blindedto treatment allocation. Data collection included patientreported Western Ontarioand McMaster Universities Osteoarthritis (WOMAC) visual analog scale (VAS)scores, Outcome Measures in Rheumatology Clinical Trials and Osteoarthritis ResearchSociety International responses (OMERACT-OARSI responses), physician and patientglobal assessments and adverse events (AEs). The primary effectiveness analysiswas a comparison, at 13 weeks, between Gel-One® and PBS treatment groups ofchange from baseline in WOMAC VAS Pain subscore, measured on a 100 mm scale.
Patient Population And Demographics
Of the 379 enrolled patients, 377 patients received eitherGel-One® or PBS injection, and 375 patients were analyzed for the Intent totreat (ITT) population. Patients reported pain with symptomatic OA of the kneedefined by WOMAC VAS Pain subscore of > 40 mm in the study knee and < 20 mmin the contralateral knee. Patients meeting the following criteria wereexcluded at randomization; Kellgren-Lawrence Grade 4, severe inflammation orjoint effusion in either knee. The ITT population included all treated patientswho had any post-injection evaluations. Table 1 summarizes baseline and patientdemographic characteristics for the ITT population.
Treatment And Evaluation Schedule
Following an initial screening visit, eligible patients wererandomized to receive either a single injection of Gel-One® or a singleinjection of PBS. Patients in both treatment groups received an intra-articularinjection in the identified knee joint at Week 0. Effectiveness and safetymeasures were assessed by follow-up visits at Weeks 1, 3, 6, 9 and 13.
Patients, who used NSAIDs at stable doses over 4 weeksprior to study injection, were allowed to continue with the same regimen.Intermittent use of short-acting opiates was allowed during the study. Acetaminophen was provided to patients as a rescue medication up to 4,000 mgper day. All medication was prohibited within 24 hours prior to each evaluationvisit.
Adverse Events Summary
Among the Gel-One® treatment group (249 patients), 483adverse events in 172 patients (69.1%) were reported. Among the PBS treatment group(128 patients), 216 adverse events in 81 patients (63.3%) were reported. Therewas no statistically significant difference in the incidence rates of adverseevents between Gel-One® and PBS treatment groups. Adverse events occurring inmore than 5% of patients in both treatment groups included joint swelling(knee), joint effusion (knee), arthralgia (knee or hip) and upper respiratorytract infections (Refer to Table 2).
The most common adverse events related to Gel-One®injection reported in this study were joint swelling (14.1%), joint effusion(11.2%), and arthralgia (7.6%).
Additional adverse events related to Gel-One® injection includedinjection site pain (2.0%), joint stiffness (0.8%), muscular weakness (0.8%),dizziness (0.8%), erythema (0.8%), effusion (0.4%), injection site bruising(0.4%), injection site erythema (0.4%), swelling (0.4%), increased alanine aminotransferase (0.4%), increased white blood cell count (0.4%), back pain (0.4%), muscle spasms(0.4%), synovitis (0.4%), tension headache (0.4%), rash (0.4%), rash pruritic (0.4%) and hypertension (0.4%) (Refer to Table 3).
There were neither serious adverse events nor pseudosepticreactions related to Gel-One® injection.
Clinical Effectiveness Results
The study primary endpoint, WOMAC Pain subscore at Week13, demonstrated that Gel-One® was superior to PBS with a 6.39 mm advantage atWeek 13 in the ITT population (p=0.0374) (Refer to Table 4 and Figure 1).
Summary of secondary effectiveness results are shown inTables 5 and 6.
Table 1. Patient Baseline Characteristics - ITTPopulation
Variable | Gel-One® (N=247) | PBS (N=128) | |
Age (years) | Mean (SD) | 60.9 (10.2) | 60.3 (10.0) |
Gender (n) | Male | 100 (40.5%) | 51 (39.8%) |
Female | 147 (59.5%) | 77 (60.2%) | |
K-L Score - Study Knee (n) | 1 | 21 (8.5%) | 18(14.1%) |
2 | 94(38.1%) | 47 (36.7%) | |
3 | 132 (53.4%) | 63 (49.2%) | |
Study Knee | |||
WOMAC Pain Subscore (mm) | Mean (SD) | 70.7 (14.4) | 68.0 (13.1) |
Total WOMAC Score (mm) | Mean (SD) | 69.5 (16.0) | 67.8 (14.7) |
WOMAC Physical Function (mm) | Mean (SD) | 68.9 (17.4) | 67.6 (15.8) |
WOMAC Stiffness (mm) | Mean (SD) | 71.6 (17.5) | 69.3 (17.3) |
Contralateral Knee | |||
WOMAC Pain Subscore (mm) | Mean (SD) | 7.3 (5.5) | 7.6 (5.6) |
Table 2. Adverse Events Occurring in ≥ 5% ofTreated Patients
System Organ Class | Preferred Term | Gel-One® (N=249) | PBS (N=128) |
Musculoskeletal and connective tissue disorders | Joint swelling (knee) | 70 (28.1%) | 36 (28.1%) |
Joint effusion (knee) | 58 (23.3%) | 33 (25.8%) | |
Arthralgia (knee/hip) | 44 (17.7%) | 15 (11.7%) | |
Infections and infestations | Upper respiratory tract infections | 16 (6.4%) | 6 (4.7%) |
Table 3. Adverse Events Related to Study Treatment
System Organ Class | Preferred Term | Gel-One® (N=249) | PBS (N=128) |
Musculoskeletal and connective tissue disorders | Joint swelling (knee) | 35 (14.1%) | 15 (11.7%) |
Joint effusion (knee) | 28 (11.2%) | 13 (10.2%) | |
Arthralgia (knee/hlp) | 19 (7.6%) | 12 (9.4%) | |
Joint stiffness (knee) | 2 (0.8%) | 1 (0.8%) | |
Muscular weakness (knee) | 2 (0.8%) | 1 (0.8%) | |
Back pain | 1 (0.4%) | 1 (0.8%) | |
Joint warmth (knee) | 0 | 1 (0.8%) | |
Muscle spasms (knee) | 1 (0.4%) | 0 | |
Synovitis (knee) | 1 (0.4%) | 0 | |
General disorders and administration site conditions | Injection site pain | 5 (2.0%) | 1 (0.8%) |
Effusion | 1 (0.4%) | 1 (0.8%) | |
Injection site erythema | 1 (0.4%) | 1 (0.8%) | |
Injection site bruising | 1 (0.4%) | 0 | |
Swelling | 1 (0.4%) | 0 | |
Skin and subcutaneous tissue disorders | Erythema | 2 (0.8%) | 0 |
Rash | 1 (0.4%) | 0 | |
Rash pruritic | 1 (0.4%) | 0 | |
Nervous system disorders | Headache | 0 | 2 (1.6%) |
Dizziness | 2 (0.8%) | 0 | |
Burning sensation | 0 | 1 (0.8%) | |
Tension headache | 1 (0.4%) | 0 | |
Investigations | Increased alanine aminotransferase | 1 (0.4%) | 0 |
Increased white blood cell count | 1 (0.4%) | 0 | |
Vascular disorders | Hypertension | 1 (0.4%) | 0 |
Ear and labyrinth disorders | Hearing impaired | 0 | 1 (0.8%) |
Infections and Infestations | Cellulitis | 0 | 1 (0.8%) |
Injury, poisoning and procedural complications | Contusion | 0 | 1 (0.8%) |
Figure 1: Improvement from Baseline in WOMAC VAS PainSubscore at Week 13 - ITT Population
Table 4. WOMACa VAS Pain Improvement from Baseline at13 weeks ( ITT Population (N=375))b
Assessed Time-point | Model-Estimated Advantage (Gel-One® - PBS) | Two- sided Lower 95% Confidence Limit (mm) | Two-sided P-value |
At Week 13 | 6.39 mm | 0.37 | 0.0374 |
a The Western Ontario and McMasterUniversities Osteoarthritis Index (WOMAC) is a set of standardizedquestionnaires used by health rofessionals to evaluate the condition ofpatients with osteoarthritis of the knee and hip. WOMAC Pain Scale is 100mm. b The analysis is based on the quadratic spline model at knot of 6weeks and at week 13 for the primary endpoint. |
Table 5: OMERACT-OARSI Responsesa - ITT Population
Odds Ratiob | Two-sided Lower 95% Confidence Limit of Odds Ratioc | Two-sided P-valued |
1.27 | 0.85 | 0.2418 |
a A subject was considered an OMERACT-OARSI'responder1 if either of the following 2 criteria were met: (1) his or her reported improvement from baseline in WOMAC VAS Pain subscore orWOMAC VAS Physical Function subscore was at least 50% and the absolute change was at least 20 mm, or (2) his or her reported improvement from baseline was at least 20% and theabsolute change was at least 10 mm for at least 2 of the following 3 measures: (a) WOMACVAS Pain subscore, (b) WOMAC VAS Physical Function subscore, (c) Subject Global Evaluation. b e (Log Odds Ratio)— 1 2 7 , based on GEE model (Log Odds Ratio)=loge [probability(responder)/ probability(non-responder)]Gei-one / [probability (responder)/probability(non-responder)]pBs c When odds ratio > 1, [probability(responder)/ probability(non-responder)Gei-one] > [probability (responder)/ probability(non-responder)pes] and thus in favor of Gel-One. d Statistically not significant |
Table 6: Summary of Secondary Effectivenessa Endpointsat Week 13 - ITT Population
Effectiveness Measuresb | Model-Estimated Advantage (Gel-One® - PBS) | Two-sided Lower 95% Confidence Limit (mm) | Two-sided P-valuec |
Total WOMAC Score | 5.64 mm | -0.20 | 0.0583 |
WOMAC Stiffness | 4.91 mm | -1.31 | 0.1216 |
WOMAC Physical Function | 5.42 mm | -0.47 | 0.0714 |
a Based on the quadratic spline model at week13. b WOMAC Scale is 100mm. c P-value was not adjusted for multiplicity of secondary endpoints. |