|E.1 Medical condition or disease under investigation
|Medical condition(s) being investigated
|Pompe Disease (also known as glycogen storage disease type II)
|Medical condition in easily understood language
|Body processes [G] - Metabolic Phenomena [G03]
|E.1.2 Medical condition or disease under investigation
|Glycogen storage disease type II
|System Organ Class
|10010331 - Congenital, familial and genetic disorders
|Condition being studied is a rare disease
|E.2 Objective of the trial
|Main objective of the trial
|To evaluate safety and tolerability of a single intravenous dose of SPK-3006 administered at escalating dose levels to participants with clinically moderate late-onset Pompe disease (LOPD).
|Secondary objectives of the trial
|To evaluate potential efficacy and bioactivity of SPK-3006.
|Trial contains a sub-study
|Principal inclusion criteria
|1. Able to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (PHI) in accordance with national and local privacy regulations;
2. Males and Females ≥18 years of age with a confirmed diagnosis (i.e. genetic testing) of late-onset Pompe disease, based on a documented deficiency of GAA enzyme activity and GAA genotyping;
3. Received ERT for at least the previous 24 months and maintained a stable dose, frequency and compliance for the past 6 months with no dose variation;
4. Have clinically moderate, late-onset Pompe disease characteristics;
a. Able to walk ≥75 meters on the 6-Minute Walk Test (assistive devices permitted) but less than 500 meters assessed at 2 timepoints prior to initiating immunosuppression (Day -6) with <10% variance between the assessments. If the variance is ≥10%, a third timepoint will be collected;
b. Percentage of the predicted FVC ≥ 30% and ≤ 80% in the upright position;
5. Agree to use reliable contraception for a minimum 6 months after administration of SPK-3006. Female candidates of child bearing potential must have a negative pregnancy test prior to initiating immunosuppression (Day -6) and on Day 0 prior to administration of SPK-3006
6. Agree to refrain from blood, plasma, platelets, egg or sperm donation during the study period
|Principal exclusion criteria
|1. Active hepatitis B and/or C; All candidates must be screened for both active hepatitis B and C, regardless of prior known history.
a. Screening for hepatitis B. All candidates must have a single sample at screening for each of the following tests: HBsAg (Hepatitis B surface antigen), anti-HBc (Total Hepatitis B core antibody), and an HBV-DNA viral assay (nucleic acid test for hepatitis B virus DNA).
i. A candidate is not eligible if either HbsAg is positive or HBV-DNA is positive/detectable.
ii. A candidate is eligible if the anti-HBc is positive and both HBsAg and HBV DNA are negative, as this would be consistent with a prior infection of hepatitis B. Anti-HBc must be obtained in all candidates to discriminate between acute infection and possible reactivation of hepatitis B during the trial in candidates with no prior history of hepatitis B.
iii. A candidate who is currently undergoing antiviral therapy for chronic hepatitis B is not eligible.
b. Screening for hepatitis C:
iv. A candidate who is currently undergoing antiviral therapy for chronic hepatitis C is not eligible.
v. All other candidates, including those who have never been treated or who have completed antiviral therapy for chronic hepatitis C must have a single HCV-RNA load assay (also referred to as a nucleic acid test [NAT] for HCV RNA) at screening.
• A candidate is not eligible if his HCV-RNA load assay is positive/detectable.
• Candidates treated with anti-viral therapy for chronic hepatitis C, must have completed anti-viral therapy at least 6 months prior to screening and have a negative HCV-RNA at the time of screening.
• Candidates with a documented or self-reported history of HCV must have a single negative HCV-RNA at time of screening.
2. Significant underlying liver disease. A candidate is not eligible if any of the following pre-existing diagnoses, which are indicative of significant underlying liver disease, are present in the medical record:
• Liver Cirrhosis;
• Portal hypertension; or
• Hepatic encephalopathy
All candidates who do not have the pre-existing diagnoses listed above must have the following assessments performed at screening:
• Measurement of serum albumin. A candidate is not eligible if the serum albumin level is below the testing laboratory’s lower limit of normal;
• Liver fibrosis ≥ stage 3. The following results are indicative of fibrosis ≥ stage 3 and exclude the candidate from participation:
- FibroScan, with a score > 8.3 kPa units
- FibroTest/ FibroSURE with a result > 0.48
- AST-Platelet Ratio Index (APRI) >1;
Of note, if results from more than one modality for evaluation of liver fibrosis are available (e.g., results from both FibroScan and FibroSURE are available) the result from FibroScan should be consulted for determination of liver fibrosis as it will take precedence over other modalities.
3. Human immunodeficiency virus infection;
4. Prior hypersensitivity to GAA;
5. Pre-existing anti-AAV neutralizing antibody titers >1:1;
6. High titer antibody responses to rhGAA (anti-GAA >1:30,000);
7. Participation in a clinical study with investigational drug in the past six months (vaccination studies are accepted; observation studies are accepted after discussion with the sponsor medical monitor);
8. Requires any invasive ventilation or requires noninvasive ventilation while awake and upright;
9. Any change to respiratory muscle strength training within 90 days prior to informed consent (for participants receiving respiratory muscle strength training) or initiation of respiratory muscle strength training Prior to Day 0;
10. Received any prior vector or gene transfer agent;
11. Concomitant use of medication that is contraindicated with sirolimus (see Section 220.127.116.11 of the protocol), such as, Medication known to be a strong or moderate inducer or inhibitor of CYP3A4 – excluded only during the sirolimus immunosuppressive period;
12. Live vaccines within 30 days prior to informed consent and for the duration of the study;
13. Use of systemic immunosuppressive agents (e.g., corticosteroids) within 30 days prior to informed consent and after informed consent prior to SPK-3006 administration;
14. Active malignancy (except non-melanoma skin cancer);
15. History of liver cancer;
16. Pregnant or nursing women;
17. Any evidence of an active infection at the time of SPK-3006 infusion;
18. Known allergy or hypersensitivity to SPK-3006 investigational product or sirolimus;
19. Any concurrent clinically significant condition that would not allow the potential participant to complete the follow-up examinations during the course of the study, or other condition that, in the opinion of the Investigator and/or Sponsor, makes the candidate unsuitable for participation in the study;
20. Unable or unwilling to comply with the visit schedule and study assessments described in the clinical protocol.
|E.5 End points
|Primary end point(s)
|• Incidence of adverse and serious adverse events (AEs/SAES), clinically significant abnormal laboratory values, change in vital signs, change in physical examination, vector shedding in bodily fluids, liver function tests
• Immune responses against AAV capsid and GAA transgene product
|Timepoint(s) of evaluation of this end point
|Evaluation of AEs and SAEs will be ongoing throughout the study.
Laboratory assessments including shedding and liver function tests will occur as detailed in the schedule of assessments in protocol SPK-3006-101.
|Secondary end point(s)
|• Changes from baseline in the Six-Minute Walk Test (6MWT)
• Changes from baseline in the Forced Vital Capacity (FVC)
• Peak and steady-state vector-derived GAA enzyme levels assessed by total GAA protein and activity measured in plasma
• Biomarkers of muscle injury and glycogen accumulation (CK, Urine Hex 4)
|Timepoint(s) of evaluation of this end point
|Designated assessments will be collected as detailed in the schedule of assessments in protocol SPK-3006-101.
|E.6 and E.7 Scope of the trial
|Scope of the trial
|Trial type and phase
|Human pharmacology (Phase I)
|First administration to humans
|Other trial type description
|Therapeutic exploratory (Phase II)
|Therapeutic confirmatory (Phase III)
|Therapeutic use (Phase IV)
|E.8 Design of the trial
|Other trial design description
| Comparator of controlled trial
|Other medicinal product(s)
The trial involves single site in the Member State concerned
| The trial involves multiple sites in the Member State concerned
|The trial involves multiple Member States
|Number of sites anticipated in the EEA
|E.8.6 Trial involving sites outside the EEA
|Trial being conducted both within and outside the EEA
|Trial being conducted completely outside of the EEA
|If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
|Trial has a data monitoring committee
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|The end of the study is defined as the date of the last visit of the last participant in the study (LVLS).
|E.8.9 Initial estimate of the duration of the trial
|In the Member State concerned years
|In the Member State concerned months
|In the Member State concerned days
|In all countries concerned by the trial years
|In all countries concerned by the trial months
|In all countries concerned by the trial days