Extension of Study TKT024 Evaluating Long-Term Safety and Clinical Outcomes in MPS II Patients Receiving Idursulfase

• Measurements of the six-minute-walk test (6-MWT) and forced vital capacity (FVC) [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  
• Collection of adverse events (including infusion-related adverse events), and changes in 12-lead ECG, vital signs, physical exams, standard laboratory parameters, and anti-idursulfase antibody status. [ Time Frame: 2+ years ] [ Designated as safety issue: Yes ]
  

• Measurements of joint range of motion (JROM) [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  
• Measurements of combined liver and spleen size [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  
• Measurements of urine GAG levels [ Time Frame: 2+ years ] [ Designated as safety issue: No ]
  
• Measurements of cardiac left ventricular mass (LVM) [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  

Study TKT024EXT was conducted in 2 phases. The first phase consisted of a 2-year period with each year consisting of 52 weekly infusions of idursulfase. Idursulfase was administered to patients as a continuous IV infusion at a dose of 0.5 mg of protein per kg of body weight (0.5 mg/kg). Certain final evaluations from Study TKT024 served as the baseline assessments for this study. Safety and efficacy outcomes were determined at 4-month intervals during the first year (ie, Weeks 18, 36, and 53) and at 6-month intervals in the second year (ie, Weeks 79 and 105). Safety and clinical outcomes were identical to those evaluated in the double-blind phase of Study TKT024. Forced vital capacity (FVC) and the 6-minute walk test (6MWT) continued to be the primary clinical outcomes of this study. Data were also collected on significant clinical events that reflect disease progression in this patient population. The focus was on events involving the major organ systems affected by MPS II: cardiac, respiratory, skeletal, and neurological.

The second phase of the study consisted of weekly infusions of IV idursulfase 0.5 mg/kg and monitoring patients for safety (via collection of adverse events, concomitant medications, and vital signs). Patients continued treatment during the second study phase until they transitioned to commercially available idursulfase or they discontinued this study for other reasons. Study completion was defined as the time a patient either transitioned to commercially available idursulfase or discontinued this study for other reasons.

Week 105 defined the beginning of the second study phase. Patients had a scheduled evaluation every 6 months until they completed or discontinued the study, including a safety evaluation (assessment of adverse events, concomitant medications, physical examination, clinical laboratory values, and anti-idursulfase antibodies), measurement of urine GAG levels, and collection of long-term clinical events. At the time a patient completed or discontinued the study, the patient should have had an "End of Study" evaluation consisting of assessment of adverse events, concomitant medications, 12-lead electrocardiogram (ECG), physical examination (including measurement of height, weight, and head circumference), clinical laboratory evaluations (including measurement of anti-idursulfase antibodies), measurement of urine GAG levels, and collection of long-term clinical events. In addition, patients who discontinued this study for reasons other than transitioning to commercially available idursulfase had an additional safety assessment 30 days after their last infusion.

To fulfill the secondary objective of this study, a commercial-scale manufacturing lot of idursulfase was introduced into the trial as soon as it was available, in order to begin generating safety data on this drug product. Pharmacokinetic (PK) data on this commercial-scale material was also obtained from the PK studies conducted during the first year of the study.

Initially, patients continued to receive their weekly infusions at the same study centers as in Study TKT024. However, based on an acceptable safety experience, patients were transitioned to investigational centers closer to their homes to receive their infusions. During the first phase of this study, patients were required to return to the main testing sites every 4 months during the first year and every 6 months during the second year for their major study evaluations. During the second phase, patients received their infusions and had all scheduled evaluations at the local clinical sites.