| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsing-remitting multiple sclerosis |
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| E.1.1.1 | Medical condition in easily understood language |
| Relapsing-remitting multiple sclerosis is a type of multiple sclerosis characterised by episodes or attacks (relapses), followed by stages of symptom subsidence after each attack (remissions). |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10063399 |
| E.1.2 | Term | Relapsing-remitting multiple sclerosis |
| E.1.2 | System Organ Class | 10029205 - Nervous system 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 |
| The primary objective of the study is to evaluate safety and tolerability as defined by the frequency of the adverse events (AEs) of flu-like symptoms (FLS) [chills, pyrexia, myalgia, and asthenia], injection site reactions (ISRs), and injection site reaction pain (ISR-P), over 24 weeks of treatment (the active comparator period) with PLEGRIDY™ 125 μg SC every 2 weeks versus current SC IFN-β therapy in subjects with RRMS. |
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| E.2.2 | Secondary objectives of the trial |
- Treatment satisfaction: To assess subject-reported treatment satisfaction using the Treatment Satisfaction Questionnaire for Medication (TSQM-9).
- Pain: To assess subject-reported pain.
- Patient-Reported Outcomes: To assess the treatments’ impact on MS using the patient-reported outcome (PRO) measures EuroQol Group 5 Dimension 3 Level Version (EQ-5D 3L), Work Productivity and Activity Impairment Questionnaire: Multiple Sclerosis V2.1 (WPAI: MS), 12-Item Short Form Survey (SF-12), Fatigue Severity Scale (FSS), Hospital Anxiety and Depression Scale (HADS);
- Treatment adherence: To assess subject adherence to study treatment;
- Clinical status: To assess subject clinical status as measured by the EDSS and relapse activity;
- Safety and tolerability: To assess subject safety and tolerability of study treatment after a change in current SC IFN-β therapy.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Ability 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 subject privacy regulations. Legally authorized representatives may provide consent for subjects unable to do so and illiterate subjects may consent verbally, in the presence of least one impartial witness.
2.Aged 18 to 65 years, inclusive, at the time of informed consent.
3.A confirmed diagnosis of RRMS, as defined by McDonald criteria (2017).
4.An EDSS score between 0 and 5.0.
5.All female subjects of childbearing potential must practice effective contraception during the study and be willing and able to continue contraception for 3 months after their last dose of study treatment.
6.On continual treatment for ≥6 months with a single current SC IFN β therapy, including IFN-β-1b 0.25 mg SC every other day or IFN-β-1a 22μg or 44 μg SC 3 times weekly
7.From a clinical perspective (as determined by the Investigator) be a candidate for switching to PLEGRIDY for RRMS treatment but able to continue current therapy (i.e., no significant untoward events attributed to IFN therapy that would preclude continuation of the existing IFN therapy).
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| E.4 | Principal exclusion criteria |
1.Unable or unwilling to provide informed consent.
2.Primary progressive, secondary progressive, or progressive relapsing MS (Lublin 1996). These conditions require the presence of continuous clinical disease worsening over a period of at least 3 months. Subjects with these conditions may also have superimposed relapse but are distinguished from subjects with relapsing MS by the lack of clinically stable periods or clinical improvement.
3.History of inadequate response to SC IFN therapy (as determined by the treating physician).
4.History or severe allergic or anaphylactic reaction or known allergy/hypersensitivity to any component of the PLEGRIDY™ formulation.
5.History of any clinically significant (as determined by the Investigator) cardiac, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, renal, or other major disease that would preclude participation in a clinical study.
6.History of malignant disease, including solid tumors and hematologic malignancies (with the exception of basal cell and squamous cell carcinomas of the skin that have been completely excised and are considered cured by the treating physician).
7.History of seizure disorder or unexplained blackouts OR history of a seizure within 3 months prior to Baseline.
8.History of suicidal ideation within 3 months prior to Baseline or an episode of severe depression within 3 months prior to Baseline. Severe depression is defined as an episode of depression that requires hospitalization, or at the discretion of the Investigator.
9.Known history of human immunodeficiency virus.
10.Known history of or positive test result for antibodies to hepatitis C, or current hepatitis B infection (defined as positive for hepatitis B surface antigen [HBsAg] and/or positive for hepatitis B core antibody [HBcAb]) at Screening. Subjects with immunity to hepatitis B from either active vaccination (defined as negative HBsAg, positive hepatitis B surface antibody [HBsAb], and negative HBcAb) or from previous natural infection (defined as negative HBsAg, positive HBsAb immunoglobulin G, and positive HBcAb) are eligible to participate in the study (definitions are based on the Centers for Disease Control and Prevention’s interpretation of the hepatitis B serology panel [CDC 2007]).
11.Abnormal screening blood tests exceeding any of the limits defined below:
- Alanine transaminase/serum glutamate pyruvate transaminase (ALT/SGPT) greater than
3 times the upper limit of normal (>3 × ULN), aspartate transaminase/serum glutamic
oxaloacetic transaminase (AST/SGOT) >3 × ULN, or bilirubin >1.5 × ULN.
- Total white blood cell count <3700/mm3.
- Absolute neutrophil count <1500/mm3.
- Platelet count <150,000/mm3.
- Hemoglobin <10 g/dL for females; <11 g/dL for males.
- Serum creatinine >ULN.
- Prothrombin time or activated partial thromboplastin time >1.2 × ULN.
12.An MS relapse that has occurred within the 50 days prior to randomization and/or lack of stabilization from a previous relapse prior to randomization (Day 1).
13.Any previous treatment with PLEGRIDY™.
14.History of hypersensitivity or intolerance to paracetamol, ibuprofen, naproxen, or aspirin that would preclude use of at least one of these during the study.
15.Treatment with other agents for MS as specified below (time off the agent is required prior to Baseline):
-Total lymphoid radiation, cladribine, 4-aminopyridine, fingolimod, T-cell or
T-cell receptor vaccine, any therapeutic monoclonal antibody (e.g., rituximab,
natalizumab, and alemtuzumab) – prior treatment(s) not allowed.
-Teriflunomide (Aubagio™)—2 years.
-Cyclophosphamide, mitoxantrone—1 year.
-Cyclosporine, plasma exchange, intravenous immunoglobulin, azathioprine,
mycophenylate, methotrexate—6 months.
-Systemic corticosteroids—50 days.
16.Treatment with medications largely dependent of the hepatic cytochrome P450 system for clearance, such as some classes of antiepileptic and antidepressant drugs.
17.Female subject is pregnant or breast-feeding.
18.Employee of the investigator or study site, with direct involvement in the proposed study or other studies under the direction of that investigator or study site, as well as family members of the employees or the investigator.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint that relates to this objective is the combined counts of AEs of FLS (chills, pyrexia, myalgia, and asthenia), ISRs (defined as a post-application assessment score ≥2 in subject and clinician assessments using the PSA and CEA scales respectively), and ISR P (defined as VAS associated with ISR ≥1 immediately after injection or 30 minutes post-injection) over the first 24 weeks of treatment with PLEGRIDY™ 125 μg SC every 2 weeks versus current SC IFN-β therapy. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Over the first 24 weeks of treatment. |
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| E.5.2 | Secondary end point(s) |
Treatment satisfaction:
·The change in subject-reported treatment satisfaction using the TSQM-9 from Baseline to the end of the comparator period in subjects treated with PLEGRIDY versus current SC IFN-β.
·The change in subject-reported treatment satisfaction using the TSQM-9 from 24 weeks through 48 weeks in subjects who switched from current SC IFN-β therapy to PLEGRIDY™ at the end of the comparator period.
Pain:
·Proportion of pain-free subjects immediately after injection at end of the comparator period in subjects treated with PLEGRIDY versus current SC IFN-β.
·Proportion of pain-free subjects 30 minutes after injection at end of the comparator period in subjects treated with PLEGRIDY versus current SC IFN-β.
·The average change in subject-reported VAS pain score from pre-injection to 30 minutes post-injection at the end of the comparator period in subjects treated with PLEGRIDY versus current SC IFN-β.
·The average change in subject-reported VAS pain score from pre-injection to immediate post-injection at the end of the comparator period in subjects treated with PLEGRIDY versus current SC IFN-β.
Patient-Reported Outcomes (PRO):
·The change in PRO measures from Baseline to the end of the comparator period, and PRO measures at week 24 in subjects treated with PLEGRIDY versus current SC IFN-β.
·The change in PRO measures from 24 weeks to 48 weeks in subjects continuously treated with PLEGRIDY™ versus subjects who switched from current SC IFN-β therapy to PLEGRIDY™ at the end of the comparator period.
·The change in PRO measures from 24 weeks to the end of the study in subjects continuously treated with PLEGRIDY™ versus subjects who switched from current SC IFN-β therapy to PLEGRIDY™ at the end of the comparator period.
·The change in PRO measures from 24 weeks to 48 weeks in subjects who switched from current SC IFN-β therapy to PLEGRIDY™ at the end of the comparator period; data from this time frame also will be compared with data obtained from Baseline to the end of the comparator period.
·The change in PRO measures from 24 weeks to the end of study in subjects who switched from current SC IFN-β therapy to PLEGRIDY™ at the end of the comparator period; data from this time frame also will be compared with data obtained from Baseline to the end of the comparator period.
Treatment adherence:
·Subject adherence to study treatment as measured by treatment adherence questionnaire at week 24 in subjects treated with PLEGRIDY versus current SC IFN-β.
·Subject adherence to study treatment as measured by returned injection pens through week 24 in subjects treated with PLEGRIDY versus current SC IFN-β.
·Subject adherence to study treatment as measured by treatment adherence questionnaire from 24 weeks through the end of the study in all subjects.
·Subject adherence to study treatment as measured by returned injection pens from 24 weeks through the end of the study in all subjects.
·Subject adherence to study treatment as measured by treatment adherence questionnaire from 24 weeks through 48 weeks and from 24 weeks through the end of study in subjects who switched from current SC IFN-β therapy to PLEGRIDY™ at the end of the comparator period; data from this time frame also will be compared with data obtained from Baseline to the end of the comparator period.
·Subject adherence to study treatment as measured by returned injection pens from 24 weeks through 48 weeks and from 24 weeks through the end of study in subjects who switched from current SC IFN-β therapy to PLEGRIDY™ at the end of the comparator period; data from this time frame also will be compared with data obtained from Baseline to the end of the comparator period.
Clinical status:
·Changes in subject clinical status, as measured by absolute change in EDSS at 48 weeks.
·Change in relapse activity as measured by change of ARR pre-study to on-study ARR.
·ARR and proportion of subjects relapsing at the end of the study in the full study population.
Safety and tolerability:
·Incidence and frequency of all subject AEs, SAEs, and discontinuations of study treatment due to an AE through the end of the comparator period in subjects treated with PLEGRIDY versus current SC IFN-β.
·Incidence and frequency of all subject AEs, SAEs, and discontinuations of study treatment due to an AE 24 weeks through 48 weeks and from 24 weeks through the end of the study in in subjects continuously treated with PLEGRIDY™ versus subjects who switched from current SC IFN-β therapy to PLEGRIDY™ at the end of the comparator period.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Treatment satisfaction: 24 weeks, 48 weeks.
Pain: 24 weeks.
Patient-Reported Outcomes: 24 weeks, 48 weeks, 72 weeks.
Treatment adherence: 24 weeks, 48 weeks, 72 weeks.
Clinical status: 48 weeks, 72 weeks.
Safety and tolerability: 24 weeks, 48 weeks, 72 weeks. |
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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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| 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 | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 17 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| 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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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
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