| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10036099 |
| E.1.2 | Term | Polymyalgia rheumatica |
| E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To show that treatment with Lodotra® (starting dose of 15 mg daily), administered in the evening, is non-inferior to treatment with prednisone IR (starting dose of 15 mg daily), administered in the morning, with regards to the percentage of complete responders to treatment 4 weeks after randomisation. |
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| E.2.2 | Secondary objectives of the trial |
1. To demonstrate superiority of Lodotra® (starting dose of 15 mg daily) to prednisone IR (starting dose of 15 mg daily) in the core phase.
2. To compare Lodotra® (starting dose of 15 mg daily) and prednisone IR (starting dose of 15 mg daily) in the core phase by means of: Level of response, Pain/Fatigue/PMR VAS, Duration of morning stiffness, Lab values for CRP and erythrocyte sedimentation rate (ESR), subject questionnaires (Health assessment questionnaire disability index (HAQ-DI); Quality of life: Short Form (SF)-36 physical component summary (PCS) and SF-36 mental component summary (MCS); EuroQol (EQ)-5D), IL-6 levels.
3. To assess the potential for dose sparing effects between Lodotra® and prednisone IR in the extension phase of the study.
4. To assess safety and tolerability in the core phase of the study and long-term safety from the extension phase by assessing AEs, vital signs (including weight), laboratory data, and electrocardiograms (ECGs). |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| pharmacogenomic sub-study: under a separate informed consent process, subjects will be invited to consent to blood sampling for pharmacogenomic testing. The blood samples will be collected at V1 and will be anonymised and stored for future analysis. The consent to pharmacogenomic sampling is completely separate from the main study and subjects will be able to take part in the main study without consenting to pharmacogenomic blood sampling. Blood sampling must take place prior to receiving any dose of study medication. |
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| E.3 | Principal inclusion criteria |
1. Males or females, 50 years of age or older who provided written informed consent.
2. Females less than one year post-menopausal must have a negative serum or urine pregnancy test recorded prior to the first dose of study medication, be non-lactating, and willing to use adequate and highly effective methods of contraception throughout the study. A highly effective method of birth control is defined as those which result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly such as sterilisation, implants, injectables, combined oral contraceptives, some IUDs (Intrauterine Device, hormonal), sexual abstinence or vasectomised partner).
3. Subjects newly diagnosed with polymyalgia rheumatica and previously untreated with glucocorticoids for PMR. The diagnosis of polymyalgia rheumatica must be confirmed by all of the following criteria:
• New onset bilateral shoulder pain or new onset bilateral shoulder and hip girdle pain.
• PMR VAS score over the last 24 hours before the Screening Visit ≥ 50 (on a 0 - 100 scale).
• Morning stiffness duration of ≥ 45 min on the day before the Screening Visit.
• Acute phase response shown by elevated C-reactive protein (CRP; ≥ 2 times ULN).
4. Subjects willing and able to participate in all aspects of the study and comply with the use of study medication.
Criteria for Entry into the Open-label Extension Phase (Re-randomisation):
1. Inclusion criteria no. 1, 2 and 4 still fulfilled.
2. None of the exclusion criteria fulfilled, except no. 17.
3. Subject demonstrates ≥ 70% improvement in PMR VAS and ≥ 70% reduction in the duration of morning stiffness from baseline (Visit 2).
4. Investigator considers subject eligible for entry into open-label phase of the study.
5. Subject is willing to enter the open-label phase of the study. |
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| E.4 | Principal exclusion criteria |
1. Females who are pregnant (positive β-hCG test) or lactating.
2. Subjects with any contraindication/history of hypersensitivity to predniso(lo)ne or other ingredients.
3. Significant renal impairment (serume creatinine > 150 µmol/L).
4. Significant hepatic impairment (ALT, AST and GGT > 2.5 ULN).
5. Subjects suffering from another disease which requires glucocorticosteroid treatment. Topical glucocorticosteroids, e.g. intra-nasal or inhaled glucocorticosteroids are allowed but should be kept at a stable dose throughout the study.
6. Continued use of systemic glucocorticoids within 4 weeks prior to the Screening Visit.
7. Joint injections with glucocorticoids within 6 weeks prior to the Screening Visit.
8. Subjects who require treatment with non-permitted concomitant therapies.
9. Evidence of clinically significant cardiovascular, renal, hepatic, gastrointestinal or psychiatric disease at the time of screening, as determined by medical history, clinical laboratory tests, ECG results, and physical examination, that would place the subject at risk upon exposure to the study medication or that may confound the analysis and/or interpretation of the study results.
10. Active alcohol or drug abuse.
11. Subjects suffering from giant cell arteritis, late onset rheumatoid arthritis or other inflammatory rheumatoid diseases.
12. Subjects suffering from drug-induced myalgia.
13. Subjects suffering from fibromyalgia
14. Subjects suffering from systemic lupus erythemathosus.
15. Subjects suffering from neurological conditions, e.g. Parkinson’s disease.
16. Subjects suffering from active cancer.
17. Subjects suffering from an active infection.
18. Subjects who participated in a clinical research study involving a new chemical entity or an experimental drug within 30 days prior to the Screening Visit. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy variable is the percentage of complete responders at week 4 of the double-blind core phase. Complete response is defined as all three of the following:
1. ≥ 70% improvement from baseline in PMR visual analogue scale (VAS).
2. ≥ 70% reduction from baseline in the duration of morning stiffness (MST).
3. ≥ 70% reduction from baseline in C-reactive protein (CRP) value or CRP value < 2 times upper limit of normal (ULN). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| after data base lock of the double-blind core phase |
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| E.5.2 | Secondary end point(s) |
Double-Blind Core Phase, key secondary variables:
• The change from baseline in PMR VAS score over the last 24 hours at week 4.
• The change from baseline in duration of morning stiffness at week 4.
• The change from baseline (Visit 1, Screening) in CRP at week 4.
• The percentage of complete responders at weeks 1 and 2.
Double-Blind Core Phase, additional secondary variables:
• The percentage of subjects at each level of response at each visit.
• The percentage of subjects with ≥ 70% improvement (response) from baseline in PMR VAS score over the last 24 hours at each visit.
• The percentage of subjects with ≥ 70% reduction (response) from baseline in duration of morning stiffness at each visit.
• The percentage of subjects with ≥ 70% reduction (response) from baseline (Visit 1, screening) in CRP or within 2 times the upper limit of normal (ULN) at each visit.
• The percentage of subjects with ≥ 70% improvement (response) from baseline in global pain VAS score over the last 24 hours at each visit.
• The percentage of subjects with ≥ 70% improvement (response) from baseline in shoulder pain VAS score over the last 24 hours at each visit.
• The percentage of subjects with ≥ 70% improvement (response) from baseline in fatigue VAS score over the last 24 hours at each visit.
• The change from baseline in PMR VAS score over the last 24 hours at Weeks 1 and 2.
• The change from baseline in PMR VAS score at awakening at each visit.
• The change from baseline in duration of morning stiffness at weeks 1 and 2.
• The change from baseline in global pain VAS score over the last 24 hours at each visit.
• The change from baseline in global pain VAS score at awakening at each visit.
• The change from baseline in shoulder pain VAS score over the last 24 hours at each visit.
• The change from baseline in fatigue VAS score over the last 24 hours at each visit.
• The change from baseline (Visit 1, Screening) in CRP at weeks 1 and 2.
• The change from baseline (Visit 1, Screening) in ESR at each visit.
• The change from baseline (Visit 1, Screening) in IL-6 levels at week 4.
• The change from baseline in HAQ-DI score at weeks 1 and 4.
• The proportion of responders in HAQ-DI at week 4 (defined as a decrease of ≥ 0.22 points from baseline).
• The change from baseline in SF-36 PCS and MCS domain scores at weeks 1 and 4.
• The change from baseline in EQ-5D index score at weeks 1 and 4.
Open-Label Extension Phase:
For the analysis of the open-label extension phase all endpoints will be considered as exploratory. The endpoints described in protocol section 8.3.2 will be assessed for the analysis of the open-label extension phase.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| after data base lock of the double-blind core phase and open label extension phase, respectively |
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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 | 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 | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 74 |
| 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 |
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| 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 | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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