Table 2 Summary of results for outcomes in MPSII patients treated with ERT
Outcome | Participants (studies) | Effect | P value | SOE | Comments |
|---|---|---|---|---|---|
Urinary GAG level (μg/mg creatinine) reduction Critical outcome for effectiveness | 103 (6) | Percent reduction from baseline at 1 yr (0.5 mg/kg W): weighted average 60% (range 43 to 80%) | Moderate | Consistent in attenuated phenotype regardless of dose or age | |
32 W 32 EOW 32 Placebo (1) | Percent reduction from baseline at 1 yr (0.5 mg/kg): W and EOW effects >placebo; W larger effect than EOW | <0.0001 0.039 | Single study | ||
32 W 32 EOW 32 Placebo (2) | Mean difference W and EOW from placebo at 1 yr: W: −207.4 (95% CI −284.8, −129.9); EOW: −173.2 (95% CI −240.8, −105.6) | Single study | |||
Liver volume Important outcome for effectiveness | 130 (3) | Percent reduction from baseline at 1 yr (0.5 mg/kg W): weighted average −25% (range −24% to −33%) | <0.002 all studies | Moderate | Remained constant for next 2 years No observed dosage association |
32 Tx/ 32 placebo (1) | Mean difference 1 yr: W: −24.5 (−28.9, −20.1); EOW: −23.2 (−27.8, −18.6) | Single study | No observed dosage association | ||
Harm: development of antibodies Critical outcome for safety | IgG 1 yr, 74 (4); 2–4 yrs, 150 (4) Neutralizing antibodies 1–2 yrs, 98 (4) | Increase in IgG at 1 and 2–4 yr (0.5 mg/kg W) by meta-analysis: 1 yr: 58% (95% CI 46–69); 2–4 yr: 33% (95% CI 20–49) Subset developing Neutralizing antibody at 0.5 mg/kg at 1–2 years (range 41–100%) | 0.019 | Moderate | More evidence is needed on specific clinical effects of different antibodies and the potential covariates (e.g., genotype) |
Harm: rates of IRRs and SAEs Critical outcomes for safety | IRR 213 (6); SAE 182 (5) | Rates of IRRs at 1 y (0.5 mg/kg): 63% (range 32–75%); Rates of SAEs at 1y (0.5 mg/kg): 13% (range 2–25%) | Low | ||
6-MWT (meters) Less important outcome for effectiveness | 32 W 32 EOW 32 Placebo (1) | Grp 1 (W) increased from 392 to 436 m (44 m) compared to placebo Grp 2 (EOW) increased 401 to 431 m (30 m) compared to placebo | 0.013 0.073 | Single Study | Other smaller studies (3) found longer distances, but were not statistically significant. 3-year follow-up of the RCT had 40% dropout |
Growth: height Important patient-centered outcome | 216 (5) | Impact of ERT on the slope of age-adjusted z-score of height expressed as a change in z-score/month (0.023, 0.038, 0.040, and −0.007) | <0.001 0.004 <0.001 NS | Low | Fifth study provided only slope after ERT with no comparator |
Pulmonary function (FVC%, normalized for age and sex) Critical outcome for effectiveness | 32 W 32 EOW 32 Placebo (4) | FVC% change 1 yr: Grp 1 (W): 55.3% increased by 2.8% Grp 2 (EOW): 55.1% increased by <0.1% FVC% change 3 yr: Study 2: 39.3% increased by 3.8% | 0.065 0.95 NS | Low | Of 3 other studies, one reported on only 4 of 11 patients, another did not test Elaprase-naive patients, and the last was a long-term follow-up of an RCT reporting only FVC |
JROM Important outcome for effectiveness/QoL | (3) | Nine measurements reported: Shoulder flexion: 94° to 110° Shoulder extension: 44° to 44° Shoulder abduction: 75° to 95° Knee flexion: 104° to 117° Knee extension: −11° to −10° Hip flexion: 89° to 103° Hip extension: 3.1° to 1.9° Elbow flexion: 121° to 122° Elbow extension: −43° to −35° | 0.07 0.94 0.13 0.47 0.88 0.03 0.75 0.83 0.63 | Insufficient | Example from Okuyama 2010. Most other studies reported only statistically significant results or specific measures that were statistically significant. Two studies apparently used different units/methods of measurements that were not compatible. Issues of multiple comparisons. Challenge to measure. |
Benefit and harm: physical disability/quality of life Critical patient-centered outcomes | 81 27 22 (4) | Improved (parents) 1.50 to 1.37 +2.9% social, −0.6% fine motor, and −2.3% language, −7% gross motor 77% progressed, 14% stable, 9% improved | 0.047 NS | Insufficient | 3 patients unable to complete Each study used completely different survey instrument(s), one of which was not previously validated. |
Cardiac function Critical outcome for effectiveness | 6 10 (3) | LVMI (g/m2): 140 to 133 LVEF%: 57 to 64% | 0.56 0.24 | Insufficient | One other study was not in Elaprase-naive patients and another reported no significant changes |
Sleep apnea Important outcome for effectiveness | 7 of 12 10 (2) | O2 desaturation events/hour: 19.2 to 2.4 O2 desaturation events/hour: 18 to 22 | NS NS | Insufficient | Although the average events/hour was reduced in one study, the change in the proportion with sleep apnea was not reported |
Long-term outcomes Critical outcomes for effectiveness | No studies addressed long-term measurable ERT outcomes | None | Examples include causes and durations of hospitalizations, common quantifiable measures of progression (e.g., frequency/severity of respiratory infections, progressive need for additional treatment or support); repeated testing for patient-centered outcomes (e.g., function, pain, quality of life); and survival |
