Clinical Trial Results:
A 24-month Multicenter, Open-label Phase II Trial Investigating the Safety and Efficacy of Repeated velmanase alfa (recombinant human alpha-mannosidase) Treatment in Pediatric Patients below 6 years of age with Alpha-Mannosidosis
|
Summary
|
|
EudraCT number |
2016-001988-36 |
Trial protocol |
DK DE AT FR IT |
Global end of trial date |
03 Jul 2020
|
|
Results information
|
|
Results version number |
v1(current) |
This version publication date |
02 Apr 2021
|
First version publication date |
02 Apr 2021
|
Other versions |
|
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
|
|||
|
Trial identification
|
|||
Sponsor protocol code |
CCD-LMZYMAA1-08
|
||
|
Additional study identifiers
|
|||
ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
|
Sponsors
|
|||
Sponsor organisation name |
Chiesi Farmaceutici S.p.A.
|
||
Sponsor organisation address |
Via Palermo 26/A, 43122, Parma, Italy,
|
||
Public contact |
Chiara Franke, Clinical Project Manager, Chiesi Farmaceutici S.p.A., 0039 3451247439, c.franke.consultant@chiesi.com
|
||
Scientific contact |
Chiara Franke, Clinical Project Manager, Chiesi Farmaceutici S.p.A., 0039 3451247439, c.franke.consultant@chiesi.com
|
||
|
Paediatric regulatory details
|
|||
Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
|
||
EMA paediatric investigation plan number(s) |
EMEA-001056-PIP02-12 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
|
Results analysis stage
|
|||
Analysis stage |
Final
|
||
Date of interim/final analysis |
01 Feb 2021
|
||
Is this the analysis of the primary completion data? |
Yes
|
||
Primary completion date |
03 Jul 2020
|
||
Global end of trial reached? |
Yes
|
||
Global end of trial date |
03 Jul 2020
|
||
Was the trial ended prematurely? |
No
|
||
|
General information about the trial
|
|||
Main objective of the trial |
The main objectives of this trial were to evaluate safety and efficacy of repeated velmanase alfa intravenous (i.v.) infusions in paediatric subjects aged less than 6 years with alpha-mannosidosis.
|
||
Protection of trial subjects |
The trial was conducted in accordance with the Declaration of Helsinki and the Good Clinical Practice guidelines, and following all other requirements of local laws. Safety was assessed at every visit in terms of physical examinations, vital signs, adverse events (AEs), laboratory evaluations (haematology, biochemistry, coagulation, urinalysis) and monitoring of immunoglobulin (Ig)G immunogenicity. Adverse events and serious AEs were assessed at the baseline visit, all dose visits and in connection with the dosing performed at evaluation visits. Electrocardiograms and echocardiograms were recorded at the baseline visit, monitored during and after infusions at dose visits and recorded at the 12 and 24 months evaluation visits, and for the subject enrolled in France, also at the 40 months evaluation visit. Weight was recorded at baseline and every 4 weeks and used for dosage calculation. Head circumference and height were recorded at baseline and evaluation visits and growth velocity was assessed throughout the study. Vital signs (heart rate, systolic and diastolic blood pressure, respiratory rate and temperature) were monitored and the subject was observed for AEs during infusions of velmanase alfa, and during the observation period after dosing. At the discretion of the Investigator, a central venous catheter could be implanted to ease administration of velmanase alfa and facilitate other i.v. procedures during the study, and anaesthesia could be used during lumbar punctures, with prothrombin time or International Normalized Ratio being assessed prior to anaesthesia. Prior medications and medical/surgical history was recorded at baseline, concomitant medications and illnesses were assessed throughout the study.
|
||
Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
12 Dec 2016
|
||
Long term follow-up planned |
No
|
||
Independent data monitoring committee (IDMC) involvement? |
No
|
||
|
Population of trial subjects
|
|||
Number of subjects enrolled per country |
|||
Country: Number of subjects enrolled |
Austria: 1
|
||
Country: Number of subjects enrolled |
Germany: 2
|
||
Country: Number of subjects enrolled |
France: 1
|
||
Country: Number of subjects enrolled |
Italy: 1
|
||
Worldwide total number of subjects |
5
|
||
EEA total number of subjects |
5
|
||
Number of subjects enrolled per age group |
|||
In utero |
0
|
||
Preterm newborn - gestational age < 37 wk |
0
|
||
Newborns (0-27 days) |
0
|
||
Infants and toddlers (28 days-23 months) |
0
|
||
Children (2-11 years) |
5
|
||
Adolescents (12-17 years) |
0
|
||
Adults (18-64 years) |
0
|
||
From 65 to 84 years |
0
|
||
85 years and over |
0
|
||
|
|||||||
|
Recruitment
|
|||||||
Recruitment details |
Overall, 6 subjects were screened according to inclusion/exclusion criteria, of these 5 subjects were enrolled in the study. Included subjects had to have a confirmed diagnosis of alpha-mannosidosis as defined by alpha-mannosidase activity in leukocytes or fibroblasts <10% of normal activity (historical data) and be aged <6 years at screening. | ||||||
|
Pre-assignment
|
|||||||
Screening details |
At the screening visit, eligible consenting subjects were identified, informed consent was obtained. The subject's ability to fulfil inclusion/exclusion criteria was evaluated, screening assessments were performed and the Investigator reviewed the results against the criteria. One subject (in Denmark) was a screen failure (exclusion criterion met). | ||||||
|
Period 1
|
|||||||
Period 1 title |
Overall trial (overall period)
|
||||||
Is this the baseline period? |
Yes | ||||||
Allocation method |
Not applicable
|
||||||
Blinding used |
Not blinded | ||||||
|
Arms
|
|||||||
|
Arm title
|
Enrolled subjects | ||||||
Arm description |
This was an open-label trial where all enrolled subjects received once weekly administration of i.v. velmanase alfa (recombinant human alpha-mannosidase). | ||||||
Arm type |
Experimental | ||||||
Investigational medicinal product name |
Velmanase alfa
|
||||||
Investigational medicinal product code |
CHFLMZYMAA1
|
||||||
Other name |
Lamzede
|
||||||
Pharmaceutical forms |
Powder for solution for infusion
|
||||||
Routes of administration |
Intravenous use
|
||||||
Dosage and administration details |
Velmanase alfa was administered as i.v. infusion once weekly at a dose of 1 mg/kg (weight recorded at first dose visit and every 4 weeks). Velmanase alfa is supplied as a freeze-dried sterile product in single use vials containing 10 mg of investigational medicinal product (IMP); each vial is to be reconstituted with 5.0 mL water for injection. Stability of the reconstituted product is 24 hours at 2-8°C and 10 hours at a maximum of 25°C. The solution should have reached room temperature prior to infusion. Vials were prepared as per the volume required for the dose of IMP 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 22.5 mL/hour. The last empty syringe was replaced with a syringe filled with 20 mL isotonic sodium chloride to infuse IMP left in the set. An i.v. catheter could be implanted to ease delivery.
|
||||||
|
|||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Baseline characteristics reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Overall trial
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
|
End points reporting groups
|
|||
Reporting group title |
Enrolled subjects
|
||
Reporting group description |
This was an open-label trial where all enrolled subjects received once weekly administration of i.v. velmanase alfa (recombinant human alpha-mannosidase). | ||
|
|||||||||||||||||
End point title |
Number of subjects with infusion-related reactions [1] | ||||||||||||||||
End point description |
An AE was defined as any untoward medical occurrence in a subject administered a medicinal product and which did not necessarily have a causal relationship with this treatment. An infusion-related reaction (IRR) was defined as an AE which occurred during or after 2 hours of infusion of velmanase alfa and which was assessed by the Investigator as being infusion-related. Reported terms for AEs were coded using the Medical Dictionary for Regulatory Activities version 19.0. Absolute counts, percentages and number of events were presented for the number of subjects with at least one IRR, tabulated by System Organ Class and Preferred Term (PT). The number of subjects experiencing events by PT is presented. A subject who experienced multiple occurrences of an AE is presented only once in the respective subject count.
|
||||||||||||||||
End point type |
Primary
|
||||||||||||||||
End point timeframe |
Data for IRRs were collected from the first infusion, for the duration of the study.
|
||||||||||||||||
| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Due to the small sample size, as per protocol, data have been presented mainly through listings and when applicable only summarised, with no inferential statistics implemented. |
|||||||||||||||||
|
|||||||||||||||||
| Notes [2] - Three subjects - 15 events: cyanosis-2, chills-3, hyperthermia-2, urticaria-5, anal pruritus-3. |
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||
End point title |
Detection of anti-velmanase alfa IgG antibodies [3] | ||||||||||
End point description |
Samples were collected for detection of anti-velmanase alfa IgG antibodies (ADAs) at baseline and every 4 weeks post-treatment for the first 3 months, then every 8 weeks. Additional samples could be collected at the Investigator's discretion when an IRR was suspected or as per clinical judgement. All IgG seropositive patients were tested for the presence of IgG neutralising antibodies to velmanase alfa. All subjects were ADA negative at study entry. The number of subjects who tested positive for ADAs during the study or remained negative throughout the study is presented. Of the subjects who seroconverted during the study, 2 subjects tested positive, then negative and then positive again during treatment; 2 subjects remained ADA positive from first detection until the end of the study.
|
||||||||||
End point type |
Primary
|
||||||||||
End point timeframe |
From baseline to the 24 months evaluation visit for 2 subjects, to 26 and a half months from baseline for 1 subject, to approximately 25 months from baseline for 1 subject, and to the 40 months evaluation visit for 1 subject.
|
||||||||||
| Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Due to the small sample size, as per protocol, data have been presented mainly through listings and when applicable only summarised, with no inferential statistics implemented. |
|||||||||||
|
|||||||||||
| Notes [4] - For ADA+ subjects, ADA concentrations ranged from below lower limit of quantification to 174 U/mL |
|||||||||||
| No statistical analyses for this end point | |||||||||||
|
|||||||||
End point title |
Change from baseline in serum oligosaccharide concentration (GlcNac[Man]2) | ||||||||
End point description |
Serum oligosaccharide concentration before and after treatment with velmanase alfa was an important biomarker used to assess the efficacy of velmanase alfa. Change from baseline in serum concentrations of serum oligosaccharides was analysed at the 6 months, 12 months, 18 months and 24 months evaluation visits, and for 1 patient, also at the 40 months evaluation visit. Change from baseline in serum concentration of GlcNac(Man)2 at the 24 months evaluation visit is reported.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Change from baseline to the 24 months evaluation visit
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Change from baseline in serum oligosaccharide concentrations (GlcNac[Man]3) | ||||||||
End point description |
Serum oligosaccharide concentration before and after treatment with velmanase alfa was an important biomarker used to assess the efficacy of velmanase alfa. Change from baseline in concentration of serum oligosaccharides was analysed at 6 months, 12 months, 18 months, 24 months, and for 1 patient, also at 40 months. Change from baseline in serum concentration of GlcNac(Man)3 at 24 months is reported.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Change from baseline to the 24 months evaluation visit
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||||||
End point title |
Number of stairs climbed during the 3-Minute Stair Climb Test | ||||||||||||
End point description |
The number of steps climbed in 3 minutes was measured at baseline and at evaluation visits at 6 months, 12 months, 18 months, 24 months and for 1 patient, at 40 months, to evaluate endurance. The 3-Minute Stair Climb Test is an indicator of functional exercise capacity. The test was administered by a certified physiotherapist in subjects from 4 years of age or when applicable according to the judgement of the Investigator. At each time point, 2 assessments were carried out on different days and the best value was evaluated for efficacy. The number of steps climbed in 3 minutes at baseline and 24 months is presented.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline to 24 months evaluation visit.
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Distance covered during the 6-Minute Walk Test | ||||||||||||
End point description |
The 6-Minute Walk Test is an indicator of functional exercise capacity measuring the distance walked (in metres) on a flat, hard, surface in a period of 6 minutes. The test evaluates the global and integrated responses of all the systems involved during exercise including the pulmonary and cardiovascular systems, systemic circulation, peripheral circulation, blood, neuromuscular units and muscle metabolism. The test was administered by a certified physiotherapist in subjects from 4 years of age, or when applicable as per the Judgement of the Investigator, and performed in accordance with the American Thoracic Society standards. In order to evaluate endurance, the test was administered on two different days at each assessment, with best value evaluated for efficacy. Assessments were performed at baseline, 6 months, 12 months, 18 months, 24 months and for 1 patient, at 40 months. The distances walked in 6 minutes at baseline and 24 months are presented.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline to the 24 months evaluation visit
|
||||||||||||
|
|||||||||||||
| Notes [5] - 4 at baseline, 3 at 24 months |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Change from baseline in V Wave threshold (automatic auditory brainstem response audiometry) | ||||||||||||
End point description |
Automatic auditory brainstem response (A-ABR) audiometry is a neurologic test of auditory brainstem function in response to auditory stimuli (click or tone pip) transmitted from an acoustic transducer (insert earphone or headphone), which generate an evoked potential. Administration and interpretation are typically performed by an audiologist. The elicited waveform response is measured by surface electrodes typically placed at the vertex of the scalp and ear lobes. The amplitude (microvoltage) of the signal is averaged and charted against time (in milliseconds). The waveform peaks are labelled I-VII. These waveforms normally occur within a 10 millisecond time period after a click stimulus presented at high intensities (70-90 decibels above normal adult hearing level [dB nHL]). The V Wave threshold was measured for each ear at baseline and evaluation visits at 12 months, 24 months and for 1 patient, at 40 months. Change from baseline in V Wave threshold at 12 months is presented.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline to 12 months evaluation visit.
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||||
End point title |
Change from baseline in serum immunoglobulin concentrations | ||||||||||||||
End point description |
Change from baseline in serum IgG, IgA and IgM concentrations were assessed at evaluation visits at 6 months, 12 months, 18 months, 24 months, and for 1 patient, at 40 months, for evaluation of subjects' immunological profiles. The change from baseline in serum Ig concentrations at 24 months is presented.
|
||||||||||||||
End point type |
Secondary
|
||||||||||||||
End point timeframe |
Baseline to the 24 months evaluation visit.
|
||||||||||||||
|
|||||||||||||||
| No statistical analyses for this end point | |||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
Data for AEs were collected from the time of informed consent, for the duration of the trial.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
The Investigator collected all AEs from spontaneous reports of subjects, and by observation and routine open questioning. Only the treatment-emergent adverse events are reported.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
19.0
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Enrolled subjects
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
This was an open-label trial where all enrolled subjects received once weekly administration of i.v. velmanase alfa (recombinant human alpha-mannosidase). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||
Substantial protocol amendments (globally) |
|||||||
| Were there any global substantial amendments to the protocol? Yes | |||||||
Date |
Amendment |
||||||
23 Oct 2017 |
Rationale was to update final selected laboratories and harmonise safety and pharmacokinetic timepoints.
Details of new Clinical Project Manager, sites/countries, safety contacts, human blood bank and finalised central laboratories were updated.
Time points for safety and pharmacokinetic assessments were harmonised; theoretical time point '22-hour post-infusion stop’ was substituted with ‘24-hour post-infusion stop’ for pharmacokinetic analysis.
The following were specified in Sections:
1.2.5, 14 and Appendix (App) 1: the trial would be conducted in compliance with current ICH E6 GCP;
2.0: primary endpoints amended to delete detection of neutralising/inhibitory antibodies, Childhood Health Assessment Questionnaire deleted as assessment of quality of life via questionnaire to parents (secondary efficacy endpoints efficacy); other sections updated as required;
3.0: magnetic resonance spectroscopy, magnetic resonance imaging (MRI) and diffusion-MRI of the brain would be performed at baseline only if historical data in the previous 3 months were not available, allowing for retrospective MRI data to be used; other sections of the protocol updated and further details on these assessments also included in Section 8.8;
7: time points for pharmacokinetic assessments and the amount of blood/cerebrospinal fluid (CSF) to be collected for various analyses specified in text/trial flow chart;
7.1.2.1: assessments at baseline would be performed over 2 weeks (instead of 1 week) and alpha-mannosidase activity in leukocytes would be evaluated only if historical data were not available;
8.1: heading updated to specify that CSF oligosaccharides would also be assessed;
9.1.3.1: blood samples for clinical laboratory evaluations would be drawn 24 hours after infusion-stop (not after start of dosing);
10.1.5: requirement for the Investigator to consult with allergic reaction expert in case of severe IRR removed;
16.1, 16.2 added, 19 modified, App II included. |
||||||
21 Jan 2019 |
New Section 8.10.2 was inserted, specifying details of planned additional blood sampling for bioanalytical assay development. The rationale was to develop a bioanalytical assay for the evaluation of the oligosaccharides content in the mononuclear cells aiming at following treatment response in a clinically relevant tissue. The Contract Research Organisation and Sponsor safety contact details were updated in Section 10.9. |
||||||
11 Apr 2019 |
Details of the new Clinical Program Leader were provided.
The laboratories involved in the additional blood sampling measurement mentioned in the previous version of the protocol were specified and details were updated in relevant sections of the protocol.
Section 10.7 was updated regarding follow-up of AEs.
Details on recording of AEs and reporting of SAEs to Sponsor were updated in Sections 10.8 and 10.9, respectively.
|
||||||
27 Apr 2019 |
Amendment number 1.0 (France) dated 12 February 2019 to Protocol Version 6.0 (dated 15 January 2019) was approved by the Agence Nationale de Sécurité du Médicament et des Produits de Santé (ANSM) on 27 April 2019. The rationale for the amendment was to extend the treatment for a further 12 months to cover the treatment for the subject enrolled in France until the availability of the drug on the French market. The IMP achieved reimbursement in France in December 2018 but was still not available on the market. Modification was required to the informed consent and the Case Report Form. Changes were made to sections of the protocol as appropriate to extend the duration of treatment for the French subject to 36 months, with addition of a final 36 months evaluation visit for performing efficacy assessments. For secondary endpoints it was specified that these included changes from baseline to 36 months for the French subject. The trial flow chart was updated to include additional dose visits, details of the evaluation visit and assessments at 36 months and specification of an end of trial visit for the French subject. |
||||||
24 Jun 2020 |
Amendment number 2.0 (France) dated 17 April 2020 to Protocol Version 7.0 (dated 30 January 2020) was approved by the Comités de Protection des Personnes on 24 June 2020. The rationale for the amendment was to extend the treatment for a further 4 months to cover the treatment for the subject enrolled in France until the coronavirus-19 (COVID-19) emergency was over. Due to the pandemic the subject could not complete the 36 months evaluation visit, and the treatment was stopped from 16 March to 20 April 2020. The sponsor assumed that the COVID-19 restrictions would be over by August 2020 and thought to extend the treatment for the French subject for a further 4 months, and add a final evaluation visit at 40 months (Week 166 +/- 5 weeks) after at least 4 weeks of treatment resumption. Modification was required to the informed consent and the Case Report Form. Changes were made to sections of the protocol as appropriate to extend the duration of treatment for the French subject to 40 months, with addition of the final evaluation visit for performing efficacy assessments. For secondary endpoints it was specified that these included changes from baseline to 40 months for the French subject. The trial flow chart was updated to include additional dose visits, details of the evaluation visit and assessments at 40 months and specification of an end of trial visit for the French subject. |
||||||
Interruptions (globally) |
|||||||
| Were there any global interruptions to the trial? Yes | |||||||
|
|||||||
Limitations and caveats |
|||||||
| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||||||
| Due to the COVID-19 pandemic, 1 patient missed 4 dose visits and performed 2 out of visit window, and the post-infusion observational period was reduced for some visits for 1 patient. Other patients had completed the study before. | |||||||
