E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Pompe Disease (also known as glycogen storage disease type II) |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Body processes [G] - Metabolic Phenomena [G03] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10053185 |
E.1.2 | Term | Glycogen storage disease type II |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | 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). |
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E.2.2 | Secondary objectives of the trial |
To evaluate potential efficacy and bioactivity of SPK-3006. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
To be eligible for participation in this study, candidates must meet the following inclusion criteria at Screening/baseline: 1. Be 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. Are male or female ≥18 years of age with a confirmed diagnosis (e.g., GAA genetic testing)of LOPD, or based on a documented deficiency of GAA enzyme activity; 3. Have received a marketed 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 and no longer improving on ERT; 4. Have clinically moderate LOPD characteristics; a. Be able to walk ≥75 meters on the 6MWT (assistive devices permitted) but less than500 meters assessed at two 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. Have a percentage of the predicted FVC ≥30% and ≤80% in the upright position; 5. Agree to use reliable contraception for a minimum of 6 months after administration of SPK-3006 or 12 weeks after the final dose of sirolimus, whichever occurs later. 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. See Section13 (Appendix 1) for guidance on reliable contraception and the definition of women of childbearing potential (WOCBP); 6. Agree to refrain from blood, plasma, platelets, egg or sperm, and organ donation after receiving SPK-3006.[PLEASE REFER TO PROTOCOL SYNOPSYS] |
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E.4 | Principal exclusion criteria |
Candidates will be excluded from study entry if any of the following existat Screening:1. Have active hepatitis B and/or C;All candidates must be screened for both active hepatitis B and C, regardless of prior knownhistory.a. Screening for hepatitis B:All candidates must have a single sample at Screening for each of the following tests:hepatitis B surface antigen (HBsAg), total hepatitis B core antibody (anti-HBc), and anucleic acid test for hepatitis B virus DNA (HBV-DNA viral assay).i. A candidate is not eligible if either HBsAg is positive or HBV-DNA ispositive/detectable.ii. A candidate is eligible if the anti-HBc is positive and both HBsAg and HBV-DNA arenegative, as this would be consistent with a prior infection of hepatitis B.Anti-HBcmust be obtained in all candidates to discriminate between acute infection and possiblereactivation of hepatitis B during the study in candidates with no prior history ofhepatitis B.iii. A candidate who is currently undergoing antiviral therapy for chronic hepatitis B isnot eligible.b. Screening for hepatitis C:i. A candidate who is currently undergoing antiviral therapy for chronic hepatitis C isnot eligible.ii. All other candidates, including those who have never been treated or who havecompleted antiviral therapy for chronic hepatitis C, must have a nucleic acid test forhepatitis C viral RNA (HCV-RNA single load assay) at Screening.• A candidate is not eligible if the HCV-RNA load assay is positive/detectable.• Candidates treated with anti-viral therapy for chronic hepatitis C, must havecompleted anti-viral therapy at least 6 months prior to Screening and have anegative HCV-RNA at Screening.• Candidates with a documented or self-reported history of hepatitis C must have asingle negative HCV-RNA at Screening.2. Have significant underlying liver disease. A candidate is not eligible if any of the followingpre-existing diagnoses, which are indicative of significant underlying liver disease, arepresent in the medical record:• Liver cirrhosis;• Portal hypertension;• Hepatic encephalopathy;Gamma-glutamyl transferase (GGT) >1.2X ULN; or• Bilirubin >1.2X ULN. Candidates with asymptomatic elevated bilirubin (e.g., Gilbertsyndrome) can be considered after discussion with the Sponsor Medical Monitor.All candidates who do not have the pre-existing diagnoses listed above must have thefollowing assessments performed at Screening Visit:• Measurement of serum albumin. A candidate is not eligible if the serumalbumin level isbelow the testing laboratory's lower limit of normal;• Liver fibrosis ≥ stage 3. The following results are indicative of fibrosis ≥ stage 3 andexclude the candidate from participation (see Steatosis Grade table below):FibroScan,with a score >8.3 kPa units if the patient has mild steatosis (Grade S1)FibroScan,with a score >9.5 kPa units if the patient has moderate steatosis(Grade S2)FibroScan, with a score >11 kPa units if the patient has severe steatosis (Grade S3)FibroTest/FibroSURE with a result >0.48AST-Platelet Ratio Index (APRI) >1; this is calculated using the following industrystandard formulation: ([AST in IU/L/AST ULN in IU/L] x 100) / (plateletcount in109/L) (Wai, 2003)NOTE: FibroScan results can be confounded by steatosis of the liver or the candidatebeing overweight. Therefore, all three tests are required to confirm the liver fibrosisstage.3. Have human immunodeficiency virus (HIV) infection;4. Have a prior hypersensitivity to rhGAA;5. Have pre-existing anti-AAV-Spark100 NAb titer >1:1;6. Have high titer antibody responses to rhGAA (anti-GAA ≥1:31,250);7. Had participated in a clinical study with an investigational drug in the past 6 months(vaccination studies are accepted; observation studies are accepted afterdiscussion with theMedical Monitor);8. Require any invasive ventilation or requires noninvasive ventilation while awake and upright;9. Had any change to respiratory muscle strength training within 90 daysprior to informedconsent (for participants receiving respiratory muscle strength training) or initiation ofrespiratory muscle strength training prior to Day 0;10. Received any prior vector or gene transfer agent;11. Require concomitant use of medication during the sirolimus immunosuppression period thatis contraindicated with sirolimus (see Section 7.6.4.1), such as a medication known to be astrong or moderate inducer or inhibitor of CYP3A4;12. Received live vaccines within 30 days prior to informed consent or plan to receive livevaccines within at least 52 weeks after receiving SPK-3006 infusion;13. Used a systemic immunosuppressive agent (e.g., corticosteroids) within 30 days prior toinformed consent and to Day 0 prior to SPK-3006 administration;14. Have an active malignancy (except non-melanoma skin cancer);[PLEASE REFER TO PROTOCOL SYNOPSYS] |
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E.5 End points |
E.5.1 | Primary end point(s) |
• Incidence of AEs and SAEs, clinically significant abnormal laboratory values, change in vital signs, change in PE, vector shedding in bodily fluids, liver function tests • Immune responses against the SPk100 capsid (neutralizing antibodies) and GAA transgene product (binding and neutralizing antibodies) |
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E.5.1.1 | 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. |
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E.5.2 | Secondary end point(s) |
• Changes from baseline in the Six-Minute Walk Test (6MWT) • Changes from baseline in in % predicted Forced Vital Capacity (FVC) • Peak and steady-state vector-derived GAA enzyme levels assessed by total GAA protein and activity measured in circulation • Biomarkers of muscle injury and glycogen accumulation (creatine kinase [CK], urine glucose tetrasaccharide [Hex 4]) |
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E.5.2.1 | 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. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | Yes |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 14 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
United Kingdom |
United States |
Denmark |
France |
Germany |
Italy |
Netherlands |
Spain |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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A participant is considered to have completed the study if he/she has completed all phases of the study including the Month 60 (Year 5)/EOS visit procedures. The end of the study is defined as the date of the last visit of the last participant in the study. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |