Vyndaqel Drug Use Investigation (Regulatory Post Marketing Commitment Plan)

An adverse drug reaction (ADR) was any untoward medical occurrence attributed to Vyndaqel capsules 20mg in a participant who received Vyndaqel capsules 20mg. A serious adverse drug reaction (SADR) was ADR resulting in any of the following outcomes or deemed significant for any other reason: results in death; is life-threatening; requires inpatient hospitalization or prolongation of hospitalization; results in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions); results in congenital anomaly/birth defect. Relatedness to Vyndaqel capsules 20mg was assessed by the physician.

Time frame: 3 years (However, the period for participants who started to receive Vyndaqel capsules 20mg after May 2018 was 1.5 years.)

Population: The safety analysis set comprised of participants who satisfied the inclusion criteria and had received Vyndaqel capsules 20mg at least once. Participants with no information of administration were excluded.

By setting death associated with transthyretin familial amyloid polyneuropathy (ATTR-PN) as events, the survival probability was estimated using the Kaplan-Meier method that treats cases who didn't have events within the observation period as censoring.

Time frame: 3 years (However, the period for participants who started to receive Vyndaqel capsules 20mg after May 2018 was 1.5 years.)

Population: The efficacy analysis set comprised of participants in the safety analysis set who had effectiveness evaluation by the physician based upon change in clinical symptoms and laboratory findings at least once. Participants with non-target diseases were excluded.

By setting death from any cause as events, the survival probability was estimated using the Kaplan-Meier method that treats cases who didn't have events within the observation period as censoring.

Time frame: 3 years (However, the period for participants who started to receive Vyndaqel capsules 20mg after May 2018 was 1.5 years.)

Population: The efficacy analysis set comprised of participants in the safety analysis set who had effectiveness evaluation by the physician based upon change in clinical symptoms and laboratory findings at least once. Participants with non-target diseases were excluded.

Summary statistics at each evaluation time point and their amounts of change from the start of treatment with Vyndaqel capsules 20mg were calculated. Higher mBMI scores indicate better nutrition status.The mean changes from baseline in modified Body Mass Index (mBMI) at Week 26, Week 52, Week 78, Week 104, Week 130, and Week 156 were presented with standard deviation.mBMI can be calculated by multiplying BMI by the serum albumin level.In Transthyretin Familial Amyloid Polyneuropathy patients, oedema and subsequent weight gain may occur, but weight changes can be corrected with a modified BMI.

Time frame: Week 26, Week 52, Week 78, Week 104, Week 130, Week 156

Population: The efficacy analysis set included participants from the safety analysis set who had at least one effectiveness evaluation by a physician based on changes in clinical symptoms and laboratory findings. Participants with non-target diseases were excluded. Among the participants in the efficacy analysis set (n=397), changes were evaluated for those with available baseline and timeframe values. The overall number of participants analyzed indicates those evaluated at week 26.

The amounts of change from baseline in the lower limbs (NIS-LL) was investigated for assessment of neurological function.The NIS-LL (Lower Limb) assessed muscle weakness, reflexes, and sensation (possible range: 0 to 88). Summary statistics at each evaluation time point and their amounts of change from the start of treatment with Vyndaqel capsules 20mg were calculated.Higher scores indicate more impaired neurological function.The mean changes from baseline in the NIS-LL at Week 78 and Week 156 were presented with standard deviation.

Time frame: Week 78, Week 156

Population: The efficacy analysis set included participants from the safety analysis set who had at least one effectiveness evaluation by a physician based on changes in clinical symptoms and laboratory findings. Participants with non-target diseases were excluded. Among the participants in the efficacy analysis set (n=397), changes were evaluated for those with available baseline and timeframe values. The overall number of participants analyzed indicates those evaluated at week 78.

The total score of neurological assessment (possible range: 0 to 294), scores of Motor, Reflexes and sensation were evaluated and summary statistics at each evaluation time point and their amounts of change from the start of treatment with Vyndaqel capsules 20mg were calculated. Higher scores indicate more decreased function.The mean changes from baseline in the total neurological assessment at Week 52 , Week 104, and Week 156 were presented with standard deviation.

Time frame: Week 52, Week 104, Week 156

Population: The efficacy analysis set included participants from the safety analysis set who had at least one effectiveness evaluation by a physician based on changes in clinical symptoms and laboratory findings. Participants with non-target diseases were excluded. Among the participants in the efficacy analysis set (n=397), changes were evaluated for those with available baseline and timeframe values. The overall number of participants analyzed indicates those evaluated at week 52.

The amounts of change from baseline in the TQOL score of the QOL-DN were used to assess quality of life .The Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) questionnaire which consists of symptoms items (1 to 7) and activities of daily living items (8 to 35) . Total Quality of Life (TQOL) (possible range: -4 to 136) in the QOL-DN was evaluated. Summary statistics at each evaluation time point and their amounts of change from the start of treatment with Vyndaqel capsules 20mg were calculated. Higher scores indicate decreased QOL.The mean changes from baseline in the TQOL score at Week 78 and Week 156 were presented with standard deviation.

Time frame: Week 78, Week 156

Population: The efficacy analysis set included participants from the safety analysis set who had at least one effectiveness evaluation by a physician based on changes in clinical symptoms and laboratory findings. Participants with non-target diseases were excluded. Among the participants in the efficacy analysis set (n=397), changes were evaluated for those with available baseline and timeframe values. The overall number of participants analyzed indicates those evaluated at week 78.

The percentage of participants were calculated in each group of ambulatory status change from the start of treatment with Vyndaqel capsules 20mg to the final evaluation time point (week 156). Ambulatory status (0, 1, 2, 3a, 3b, 4) was assessed using the ambulatory ability scale. The ambulatory ability scale in the polyneuropathy dysfunction score was defined as follows. Ambulatory status 0：Walking ability is Good. Ambulatory status 1：Walking ability is able to walk without difficulty despite of sensory disorder in the lower extremities. Ambulatory status. Ambulatory status 2：Walking ability is able to walk without assistance despite of some difficulties. Ambulatory status 3a：Walking ability is able to walk with one stick or crutch. Ambulatory status 3b：Walking ability is able to walk with two sticks or crutches. Ambulatory status 4: Walking ability is unable to walk, restricted to wheelchair or bedridden.

Time frame: Week 156

Population: The efficacy analysis set included participants from the safety analysis set who had at least one effectiveness evaluation by a physician based on changes in clinical symptoms and laboratory findings. Participants with non-target diseases were excluded. Among the participants in the efficacy analysis set (n=397), changes were evaluated for those with available baseline and week 156(n=214).