rhLAMAN-09

Chiesi Farmaceutici S.p.A

Via Palermo 26/A, Parma, Italy, 43122

Chiesi Clinical Trial, Chiesi Farmaceutici S.p.A, 0039 05212791, clinicaltrials_info@chiesi.com

Chiesi Clinical Trial, Chiesi Farmaceutici S.p.A, 0039 05212791, clinicaltrials_info@chiesi.com

No

No

Yes

Final

21 Apr 2023

Yes

30 Sep 2022

Yes

30 Sep 2022

No

Primary objective: evaluation of safety of repeated velmanase alfa intravenous (i.v.) treatment of subjects with alpha-mannosidosis; monitoring long-term safety profile including immunogenicity (anti-immunoglobulin (Ig)G) anti-drug antibodies (ADAs)). Secondary objectives: evaluating long-term efficacy of velmanase alfa on endurance (6-Minute Walk Test (6MWT), 3-Minute Stair Climb Test (3MSCT)), pulmonary function, serum oligosaccharides, hearing, cognitive development (Leiter International Performance Scale - Revised), motor proficiency (Bruininks-Oseretsky Test of Motor Proficiency, 2nd edition), quality of life (Childhood Health Assessment Questionnaire (CHAQ), EuroQoL-5 Dimensions 5-Levels Questionnaire), cerebrospinal fluid (CSF) and 24-hour urine oligosaccharides, central nervous system involvement (imaging and CSF biomarkers (tubulin associated unit, neurofilament light and glial fibrillary acidic proteins)), in vivo biological activity and evaluating pharmacokinetics.

The trial was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines, and following all other requirements of local laws. Subjects who had enrolled in earlier velmanase alfa trials (rhLAMAN-02/-03/-04 and rhLAMAN-05) were enrolled. Adverse events (AEs) including infusion-related reactions were collected at every visit. Other safety assessments (performed as per the trial flow chart) included laboratory evaluations (haematology, biochemistry, urinalysis, coagulation tests), physical examination, recording of vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate and body temperature), tests for ADAs and neutralising antibodies (every 12 weeks) and serum IgG/IgM/IgA (every 24 weeks). Electrocardiograms (ECGs) and echocardiograms were recorded at a comprehensive evaluation visit (CEV) performed by 7 subjects who had enrolled in earlier trials. At dosing visits, medical personnel continuously observed subjects until 1 hour post-infusion; observation periods were prolonged if required. Medical/surgical history was recorded at screening. Concomitant medications were collected throughout the trial. During the coronavirus disease 2019 (COVID-19) pandemic, a contingency plan was developed for protection of subjects in treatment phase and appropriate mitigation actions were adopted according to local regulations. As onsite visits were on hold, site staff performed weekly phone calls to obtain information on active subject status, AEs and concomitant medications.

10 Jun 2013

No

No

Denmark: 8

8

8

0

0

0

0

3

2

3

0

0

Overall trial (overall period)

Not applicable

Not applicable, open-label trial.

Velmanase alfa

CHFLMZYM

Lamzede

Powder for solution for infusion

Intravenous use

Velmanase alfa was administered as i.v. infusion once weekly at a dose of 1 mg/kg (weight recorded at first dose and every 4 weeks during the trial). An i.v. catheter could be implanted to ease delivery. The IMP is supplied as a sterile freeze-dried product in single use vials containing 10 mg, each to be reconstituted with 5.0 mL sterile water for injection. Stability of the reconstituted product is 24 hours at 5°C±3°C and 10 hours at a maximum of 25°C. The solution should reach room temperature prior to infusion. Vials were prepared as per the volume required for the dose and swirled with slow rotations for 10-15 seconds after reconstitution. The required volume was withdrawn into one or more large-dose syringes and an infusion set with a mounted filter was filled. The maximum infusion rate was 25 ml/hour. The last empty syringe was replaced with a syringe filled with 20 mL isotonic sodium chloride to infuse the product left in the set.

Overall trial (overall period)

Paediatric subjects

Enrolled subjects who were <18 years old at treatment baseline (i.e. when they received the first ever dose of velmanase alfa including in earlier trials rhLAMAN-02 and rhLAMAN-05).

Adult subjects

Enrolled subjects who were ≥18 years old at treatment baseline (i.e. when they received the first ever dose of velmanase alfa including in earlier trials rhLAMAN-02 and rhLAMAN-05).

Enrolled subjects

Paediatric subjects

Enrolled subjects who were <18 years old at treatment baseline (i.e. when they received the first ever dose of velmanase alfa including in earlier trials rhLAMAN-02 and rhLAMAN-05).

Adult subjects

Enrolled subjects who were ≥18 years old at treatment baseline (i.e. when they received the first ever dose of velmanase alfa including in earlier trials rhLAMAN-02 and rhLAMAN-05).

An adverse drug reaction (ADR) was an AE assessed to be related to study treatment by the Investigator. An IRR was defined as an ADR which occurred during or within 2 hours after the end of the infusion of velmanase alfa and was assessed by the Investigator as being infusion-related. The AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA) Version 23.0. The IRRs were summarised by System Organ Class and Preferred Term (PT) overall and by age group. The number of subjects experiencing events is presented by PT.

Primary

Data for IRRs were collected from enrolment in rhLAMAN-09 until the end of trial.

Detection of ADAs was part of the primary objective and a safety endpoint. Blood samples were collected for ADA assessments pre-infusion during the CEV and every 12 weeks during dose visits. For subjects who had received placebo during rhLAMAN-05, the first ADA assessment was considered as treatment baseline but only if captured not more than 7 days after the first study treatment administration. Subjects were considered to be ADA-positive if they were positive at treatment baseline or had an ADA-positive test at least once during rhLAMAN-09. Subjects were considered to be ADA-negative if they had no ADA-positive tests. At treatment baseline, 6 subjects were ADA-negative and 2 subjects were ADA-positive. The number of subjects who were ADA-positive/negative as defined above, is presented.

Primary

At treatment baseline (i.e. prior to first ever dose of velmanase alfa including in previous trials) and during rhLAMAN-09.

Treatment baseline was the last non-missing value before first ever dose of velmanase alfa (including in previous trials if the subject was treated, or in rhLAMAN-09 if the subject received placebo in rhLAMAN-05). Assessments during treatment were assigned to a time point (calculation: date of assessment - date of first ever dose of velmanase alfa)+1). Windowing was performed using the calculated day and a window built around a target day. If >1 time point was reported in the same window, the average of all values was considered in the analysis. Mean (SD) treatment baseline values for enrolled, paediatric and adult subjects were 6.388 (2.232), 7.440 (2.207) and 4.633 (0.551) μmol/L, respectively. For 132-204 and 228-372 weeks, no data were available for any subject. For 60-84, 108-132 and 612-636 weeks, data were available for only 1 enrolled subject (therefore data not shown below). Paired t-test and linear mixed model analyses were performed.

Secondary

Treatment baseline to time windows from start of treatment (0-12 weeks and 24-weekly intervals thereafter until end of trial).

The mean (SD) treatment baseline values for enrolled, paediatric and adult subjects were 10.900 (3.944), 12.340 (4.474) and 8.500 (0.755) μmol/L, respectively.

Secondary

The CEV was performed a mean of 2.5 years from treatment baseline. Absolute change in CSF oligosaccharide concentration from treatment baseline to the CEV was analysed.

Treatment baseline values were available for 2 subjects who were in the paediatric age group (mean (SD) of 904.500 (239.709) µmol/L).

Secondary

The CEV was performed a mean of 2.5 years from treatment baseline. Absolute change in oligosaccharides in 24-hour urine from treatment baseline to the CEV was analysed.

Treatment baseline was the last non-missing value before first ever dose of velmanase alfa (including in previous trials if the subject was treated, or in rhLAMAN-09 if the subject received placebo in rhLAMAN-05). Assessments during treatment were assigned to a time point (calculation: date of assessment - date of first ever dose of velmanase alfa)+1). Windowing was performed using the calculated day and a window built around a target day. Six months (183 days) to 365 days were accepted between yearly evaluation visits (rhLAMAN-09); dates >365 days+183 days after a visit belonged to the subsequent visit and dates <183 days from a visit belonged to that visit. Average values were used for analysis if >1 time point was reported in the same window for a subject. Mean (SD) treatment baseline values for enrolled, paediatric and adult subjects were 444.0 (135.0), 411.8 (143.4) and 497.7 (125.7) metres, respectively. Paired t-test and linear mixed model analyses were performed.

Secondary

Treatment baseline to 0-6, 6-18, 18-36, 36-60, 60-84, 84-108, 108-132 and 132-156 months (i.e. post-treatment baseline and 1, 2, 4, 6, 8, 10 and 12 years, respectively) from start of treatment.

Treatment baseline was the last non-missing value before first ever dose of velmanase alfa (including in previous trials if the subject was treated, or in rhLAMAN-09 if the subject received placebo in rhLAMAN-05). Assessments during treatment were assigned to a time point (calculation: date of assessment - date of first ever dose of velmanase alfa)+1). Windowing was performed using the calculated day and a window built around a target day. Six months (183 days) to 365 days were accepted between the yearly evaluation visits (rhLAMAN-09); dates >365 days+183 days after a visit belonged to the next visit and dates <183 days from a visit belonged to that visit. Average values were used for analysis if >1 time point was reported in the same window for a subject. Mean (SD) treatment baseline results for enrolled, paediatric and adult subjects were 51.92 (16.85), 49.73 (19.05) and 55.56 (15.36) steps/minute, respectively. Paired t-test and linear mixed model analyses were performed.

Secondary

Treatment baseline to 0-6, 6-18, 18-36, 36-60, 60-84, 84-108, 108-132 and 132-156 months (i.e. post-treatment baseline and 1, 2, 4, 6, 8, 10 and 12 years, respectively) from start of treatment.

Treatment baseline was the last non-missing value before first ever dose of velmanase alfa (including in previous trials if the subject was treated, or in rhLAMAN-09 if the subject received placebo in rhLAMAN-05). Assessments during treatment were assigned to a time point (calculation: date of assessment - date of first ever dose of velmanase alfa)+1). Windowing was performed using the calculated day and a window built around a target day. Six months (183 days) to 365 days were accepted between the yearly evaluation visits (rhLAMAN-09); dates >365 days+183 days after a visit belonged to the next visit and dates <183 days from a visit belonged to that visit. Average values were used for analysis if >1 time point was reported in the same window for a subject. Mean (SD) treatment baseline values for enrolled, paediatric and adult subjects were 2.334 (1.041), 1.804 (0.884) and 3.217 (0.600) litres, respectively. Paired t-test and linear mixed model analyses were performed.

Secondary

Treatment baseline to 0-6, 6-18, 18-36, 36-60, 60-84, 84-108, 108-132 and 132-156 months (i.e. post-treatment baseline and 1, 2, 4, 6, 8, 10 and 12 years, respectively) from start of treatment.

Treatment baseline was the last non-missing value before first ever dose of velmanase alfa (including in previous trials if the subject was treated, or in rhLAMAN-09 if the subject received placebo in rhLAMAN-05). Assessments during treatment were assigned to a time point (calculation: date of assessment - date of first ever dose of velmanase alfa)+1). Windowing was performed using the calculated day and a window built around a target day. Six months (183 days) to 365 days were accepted between the yearly evaluation visits (rhLAMAN-09); dates >365 days+183 days after a visit belonged to the next visit and dates <183 days from a visit belonged to that visit. Average values were used for analysis if >1 time point was reported in the same window for a subject. Mean (SD) treatment baseline values for enrolled, paediatric and adult subjects were 83.5 (22.8)%, 80.1 (25.3)% and 89.0 (21.7)%, respectively. Paired t-test and linear mixed model analyses were performed.

Secondary

Treatment baseline to 0-6, 6-18, 18-36, 36-60, 60-84, 84-108, 108-132 and 132-156 months (i.e. post-treatment baseline and 1, 2, 4, 6, 8, 10 and 12 years, respectively) from start of treatment.

Treatment baseline was the last non-missing value before first ever dose of velmanase alfa (including in previous trials if the subject was treated, or in rhLAMAN-09 if the subject received placebo in rhLAMAN-05). Assessments during treatment were assigned to a time point (calculation: date of assessment - date of first ever dose of velmanase alfa)+1). Windowing was performed using the calculated day and a window built around a target day. Six months (183 days) to 365 days were accepted between the yearly evaluation visits (rhLAMAN-09); dates >365 days+183 days after a visit belonged to the next visit and dates <183 days from a visit belonged to that visit. Average values were used for analysis if >1 time point was reported in the same window for a subject. Mean (SD) treatment baseline values for enrolled, paediatric and adult subjects were 2.076 (0.972), 1.608 (0.828) and 2.857 (0.690) litres, respectively. Paired t-test and linear mixed model analyses were performed.

Secondary

Treatment baseline to 0-6, 6-18, 18-36, 36-60, 60-84, 84-108, 108-132 and 132-156 months (i.e. post-treatment baseline and 1, 2, 4, 6, 8, 10 and 12 years, respectively) from start of treatment.

Treatment baseline was the last non-missing value before first ever dose of velmanase alfa (including in previous trials if the subject was treated, or in rhLAMAN-09 if the subject received placebo in rhLAMAN-05). Assessments during treatment were assigned to a time point (calculation: date of assessment - date of first ever dose of velmanase alfa)+1). Windowing was performed using the calculated day and a window built around a target day. Six months (183 days) to 365 days were accepted between the yearly evaluation visits (rhLAMAN-09); dates >365 days+183 days after a visit belonged to the next visit and dates <183 days from a visit belonged to that visit. Average values were used for analysis if >1 time point was reported in the same window for a subject. Mean (SD) treatment baseline values for enrolled, paediatric and adult subjects were 78.2 (16.7)%, 74.3 (11.8)% and 84.7 (24.4)%, respectively. Paired t-test and linear mixed model analyses were performed.

Secondary

Treatment baseline to 0-6, 6-18, 18-36, 36-60, 60-84, 84-108, 108-132 and 132-156 months (i.e. post-treatment baseline and 1, 2, 4, 6, 8, 10 and 12 years, respectively) from start of treatment.

Treatment baseline was the last non-missing value before first ever dose of velmanase alfa (including in previous trials if the subject was treated, or in rhLAMAN-09 if the subject received placebo in rhLAMAN-05). Assessments during treatment were assigned to a time point (calculation: date of assessment - date of first ever dose of velmanase alfa)+1). Windowing was performed using the calculated day and a window built around a target day. Six months (183 days) to 365 days were accepted between the yearly evaluation visits (rhLAMAN-09); dates >365 days+183 days after a visit belonged to the next visit and dates <183 days from a visit belonged to that visit. Average values were used for analysis if >1 time point was reported in the same window for a subject. Mean (SD) treatment baseline values for enrolled, paediatric and adult subjects were 4.166 (2.540), 3.032 (1.849) and 6.057 (2.676) litres per second, respectively. Paired t-test and linear mixed model analyses were performed.

Secondary

Treatment baseline to 0-6, 6-18, 18-36, 36-60, 60-84, 84-108, 108-132 and 132-156 months (i.e. post-treatment baseline and 1, 2, 4, 6, 8, 10 and 12 years, respectively) from start of treatment.

Treatment baseline was the last non-missing value before first ever dose of velmanase alfa (also in previous trials if the subject was treated, or in rhLAMAN-09 if the subject received placebo in rhLAMAN-05). Assessments during treatment were assigned to a time point (calculation: date of assessment - date of first ever dose of velmanase alfa)+1). Windowing was performed using the calculated day and a window built around a target day. Six months (183 days) to 365 days were accepted between the yearly evaluation visits (rhLAMAN-09); dates >365 days+183 days after a visit belonged to the next visit and dates <183 days from a visit belonged to that visit. Average values were used for analysis if >1 time point was reported in the same window for a subject. Mean (SD) treatment baseline scores for enrolled, paediatric and adult subjects were 1.422 (0.853), 1.350 (1.112) and 1.542 (0.191), respectively. The CHAQ Disability Index is scored 0-3 with higher scores indicating greater disability.

Secondary

Treatment baseline to 0-6, 6-18, 18-36, 36-60, 60-84, 84-108, 108-132 and 132-156 months (i.e. post-treatment baseline and 1, 2, 4, 6, 8, 10 and 12 years, respectively) from start of treatment.

Treatment baseline was the last non-missing value before first ever dose of velmanase alfa (including in previous trials if the subject was treated, or in rhLAMAN-09 if the subject received placebo in rhLAMAN-05). Assessments during treatment were assigned to a time point (calculation: date of assessment - date of first ever dose of velmanase alfa)+1). Windowing was performed using the calculated day and a window built around a target day. Six months (183 days) to 365 days were accepted between the yearly evaluation visits (rhLAMAN-09); dates >365 days+183 days after a visit belonged to the next visit and dates <183 days from a visit belonged to that visit. Average values were used for analysis if >1 time point was reported in the same window for a subject. Mean (SD) treatment baseline scores for enrolled, paediatric and adult subjects were 0.675 (0.496), 0.522 (0.450) and 0.930 (0.546), respectively. The CHAQ VAS Pain is scored 0 (no pain) to 3 (very severe pain).

Secondary

Treatment baseline to 0-6, 6-18, 18-36, 36-60, 60-84, 84-108, 108-132 and 132-156 months (i.e. post-treatment baseline and 1, 2, 4, 6, 8, 10 and 12 years, respectively) from start of treatment.

Treatment baseline was the last non-missing value before first ever dose of velmanase alfa (also in previous trials if the subject was treated, or in rhLAMAN-09 if the subject received placebo in rhLAMAN-05). Assessments during treatment were assigned to a time point (calculation: date of assessment - date of first ever dose of velmanase alfa)+1). Windowing was performed using the calculated day and a window built around a target day. Six months (183 days) to 365 days were accepted between the yearly evaluation visits (rhLAMAN-09); dates >365 days+183 days after a visit belonged to the next visit and dates <183 days from a visit belonged to that visit. Average values were used for analysis if >1 time point was reported in the same window for a subject. Mean (SD) treatment baseline scores for enrolled, paediatric and adult subjects were 0.668 (0.546), 0.480 (0.603) and 0.980 (0.284), respectively. The CHAQ VAS General is scored 0-3 with higher scores indicating poorer quality of life.

Secondary

Treatment baseline to 0-6, 6-18, 18-36, 36-60, 60-84, 84-108, 108-132 and 132-156 months (i.e. post-treatment baseline and 1, 2, 4, 6, 8, 10 and 12 years, respectively) from start of treatment.

Treatment-emergent adverse events (TEAEs) were collected from the time of informed consent in rhLAMAN-09, for the duration of the trial.

All TEAEs were collected from spontaneous, unsolicited reports of subjects, by observation and by routine open questioning.

23.0

Enrolled subjects

Paediatric subjects

Adult subjects