Safety results
The proportion of patients reporting adverse events was greatest in the twohighest dose groups (Table
5). Serious adverse events and withdrawals due to adverse events occurred with the highest frequency in the 200-mg group, in which adverse events were the primary cause of withdrawal. The majority of adverse events, serious adverse events, and withdrawals due to adverse events were musculoskeletal and connective tissue disorders. Arthralgia was the single most frequent adverse event overall (35% of all patients) and was also the most frequent serious adverse event and reason for withdrawal. Two patients, one in the 100-mg group and one in the 200-mg group, died of pulmonary embolism and cardiac failure, respectively, during the study. The investigators considered their deaths to be unrelated to study drug.
Table 5
Summary of adverse events (intent-to-treat population)
Patients with adverse events, number (percentage) | 52 (68%) | 51 (64%) | 51 (65%) | 62 (78%) | 62 (78%) |
Patients who withdrew, number (percentage) | 8 (10%) | 15 (19%) | 13 (16%) | 16 (20%) | 60a (76%) |
Patients with serious adverse events, number (percentage) | 8 (10%) | 7 (9%) | 12 (15%) | 10 (13%) | 17 (22%) |
Patients who died, number (percentage) | 0 (0%) | 0 (0%) | 0 (0%) | 1 (1%) | 1 (1%) |
Objective monitoring of musculoskeletal toxicity included goniometer assessment of shoulder ROM at each visit. Of the 391 patients who had at least onevalid shoulder ROM measurement during a follow-up visit, 90 (23%) had a decrease of at least 30% from baseline for at least one ROM measurement of either shoulder (Table
6). The percentage of patients with changes in ROM was statistically significantly greater in the twohighest dose groups relative to placebo. Twenty-nine patients (7%) had an ROM decrease of at least 30% in both shoulders. Reproducibility of the decrease in shoulder ROM (that is, decrease of 30% in a measurement at twoconsecutive visits) was used as a practical measure of specificity of the finding. Of 376 patients with valid measurements, 40 patients (11%) had a decrease of at least 30% in the same measurement for either shoulder at twoor more consecutive visits. The decrease mostly affected shoulder internal and external rotations; fewer patients had decreases in shoulder abduction and anterior flexion. Finally, 34 of 391 patients (9%) had decreases of at least 30% in two or more ROM measurements of either shoulder at the same visit. The percentage of patients with two or more ROM decreases in the twohighest dose groups was statistically significantly greater relative to placebo (Table
6).
Table 6
Changes from baseline in shoulder range of motion (intent-to-treat population)
Patients with ≥30% decrease from baseline in ≥1 ROM measurement at any postbaseline visit for either shoulder, number (percentage) | 12/77 (16%) | 11/79 (14%) | 18/78 (23%) | 24/79 (30%) | 25/78 (32%) |
P valuea | | 0.824 | 0.310 | 0.036 | 0.023 |
Patients with ≥30% decrease from baseline in the same ROM measurement at 2 or more consecutive postbaseline visits for either shoulder, number (percentage) | 4/74 (5%) | 5/78 (6%) | 8/74 (11%) | 12/77 (16%) | 11/73 (15%) |
P valuea | | 1.000 | 0.367 | 0.062 | 0.061 |
Patients with ≥30% decrease from baseline in 2 or more ROM measurements at the same postbaseline visit for either shoulder, number (percentage) | 2/77 (3%) | 2/79 (3%) | 5/78 (6%) | 13/79 (16%) | 12/78 (15%) |
P valuea | | 1.000 | 0.442 | 0.005 | 0.009 |
Adverse events affecting the hand were reported in 52 of 395 patients (13%), nearly half of whom were in the 200-mg group (Table
7). Common signs included hand oedema (5 patients), palmar fibrosis (15 patients), Dupuytren contracture (5 patients), and tendon thickening/nodules (3 patients). Most patients with hand involvement (16 patients) had asymptomatic nodules without function loss (contracture), hand pain, or hand oedema. Of the 7 symptomatic patients, 4 were in the 200-mg group, 2 in the 100-mg group, and 1 in the 50-mg group. A mild function loss in hands (mild contracture) was reported in 5 symptomatic patients, 2 of whom had accompanying pain and localized oedema, which were not reported as separate adverse events. Two other symptomatic patients included 1 patient with mild hand pain (localized hypersensitivity) and another patient with pain and oedema in the hand without any functional loss. The first cases of palmar fibrosis appeared at month3, and the number of affected patients in the 200-mg dose group reached statistical significance versus placebo at month9 (18% versus 1%;
p = 0.001). The finding of fibrosis on hand palpation was confirmed by hand ultrasound in 20 patients. Ultrasound was not a scheduled procedure in the study protocol. The usual appearance of fibrosis on ultrasound consisted of elongated or oblique bands along flexor tendons, in their proximity but not within the tendons. Their size varied depending on the examination technique (palpation versus ultrasound) and ranged from a few millimeters to approximately 2 cm in length. In one case, a thickening of fascia palmaris of 6 cm in length was described.
Table 7
Patients with hand adverse events (intent-to-treat population)
Patients with hand adverse events, number (percentage) | 5/77 (6%) | 8/80 (10%) | 9/79 (11%) | 7/80 (9%) | 23/79 (29%) |
Patients with particular hand findings (hand oedema overlapped with other findings), number | | | | | |
Hand oedema | 0 | 0 | 1 | 1 | 3 |
Palmar fibrosis | 0 | 1 | 1 | 2 | 12 |
Dupuytren contracture | 0 | 1 | 0 | 3 | 1 |
Tendon thickness/nodules | 0 | 0 | 0 | 0 | 2 |
Symptomatic patients, number | 0 | 0 | 1 | 2 | 4 |
The threemost frequent shoulder adverse events were arthralgia, stiffness, and myalgia. The first cases of shoulder arthralgia, which affected either shoulder with similar frequency, appeared after 1 month of dosing. Over the course of the whole study, 13%, 16%, 13%, 21%, and 25% of patients, respectively, in the placebo, 25-mg, 50-mg, 100-mg, and 200-mg dose groups reported shoulder arthralgia. Shoulder stiffness, which was usually isolated but sometimes accompanied by stiffness in other joints, was reported starting at month6. Over the course of the study, 1%, 4%, 6%, 9%, and 6% of patients, respectively, in the placebo, 25-mg, 50-mg, 100-mg, and 200-mg groups reported shoulder stiffness. Shoulder myalgia generally affected the deltoid muscle and was reported in 1%, 1%, 4%, 3%, and 6% of patients, respectively, in the placebo, 25-mg, 50-mg, 100-mg, and 200-mg groups over the course of the study. The threemost frequently reported shoulder adverse events could represent different reporting of a similar symptomatology. An analysis combining the threemost frequent shoulder adverse events showed a dose-related response starting after 3 months of dosing, continuing through months6 and 9, and disappearing at month 12 (data not shown).
Other symptoms included neck pain (3%, 4%, 4%, 6%, and 10% of patients, respectively, in the placebo, 25-mg, 50-mg, 100-mg, and 200-mg groups), which could be due to referred pain originating in the shoulder, and shoulder periarthritis (1%, 3%, 1%, 4%, and 6% of patients, respectively, in the placebo, 25-mg, 50-mg, 100-mg, and 200-mg groups). Shoulder ultrasounds were performed at the investigator's discretion in some symptomatic patients. Of 13 symptomatic patients in whom rotator cuff rupture (partial or complete tear) was found on shoulder ultrasound during the study, 3 patients each were in the placebo, 50-mg, 100-mg, and 200-mg groups and 1 patient was in the 25-mg group. Few patients (7%) had a combination of shoulder and hand symptoms that appeared independent of each other.
Most patients withdrawn from the study because of development of musculoskeletal adverse events were followed until resolution or stabilization of symptoms. Cessation of MMP inhibitor administration seemed to bring symptomatic relief as well as improvement in ROM in patients with shoulder involvement. Among 19 patients followed up for clinically significant shoulder involvement, the improvement was complete in 10 patients after a mean period of 122 days and partial in 3 patients after a mean period of 107 days (partial means that the symptoms or signs decreased but never returned to baseline status) (Table
8). Additionally, 3 patients with shoulder involvement recovered completely while still exposed to active drug and 3 other patients recovered partially. Complete recovery was seemingly promoted by local glucocorticoid injections in 4 patients and physiotherapy in 5 patients. Partial recovery was promoted by local glucocorticoid injections in 1 patient and physiotherapy in another patient. Patients were also administered NSAIDs and paracetamol for the shoulder symptoms or index knee OA. Recovery from shoulder symptoms was faster in patients who were exposed to the MMP inhibitors for a shorter period of time. Six patients with shoulder involvement underwent temporary drug interruption followed by drug rechallenge. The symptoms recurred in 4 of these patients. Of the 21 patients followed for hand adverse events, only 2 recovered completely after a mean period of 224 days from their last dose of study drug. Eleven patients recovered partially after a mean period of 210 days and the hand fibrosis was unchanged in 7 patients after a mean period of 196 days after stopping the study drug (partial recovery means that either the symptoms decreased or the extent of fibrosis decreased in size in clinical or ultrasound assessment) (Table
8). Of the 3 patients followed for involvement of both shoulders and hands, 2 patients recovered partially after a mean period of 170 days from the last dose of study drug (partial recovery means that symptoms or signs in at least one site of involvement, usually the shoulder, decreased). Additionally, 1 patient with both shoulder and hand involvement recovered partially while still taking active drug. Initial symptoms of hand pain or oedema, which accompanied the diagnosis of hand fibrosis, tended to disappear after stopping study drug.
Table 8
Follow-up data after PG-116800 withdrawal in patients with clinically significant shoulder findings and hand adverse events
Shoulder | Complete | 10 | 122 | 81 | 5 | 316 | Additional 3 patients recovered while still on drug |
| Partial | 3 | 107 | 138 | 30 | 154 | Additional 3 patients recovered while still on drug |
| Unchanged vs. baseline | 0 | | | | | |
Hand | Complete | 2 | 224 | 224 | 163 | 285 | |
| Partial | 12 | 210 | 213 | 93 | 329 | |
| Unchanged vs. baseline | 7 | 196 | 184 | 77 | 303 | |
Both | Complete | 0 | | | | | |
| Partial | 2 | 170 | 170 | 79 | 261 | Additional 1 patient recovered while still on drug |
| Unchanged vs. baseline | 0 | | | | | |