| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Peripheral arterial occlusive disease (PAOD, femoro-popliteal stenosis) and intermittent claudication (Fontaine stage IIb, pain-free walking distance < 200 m), lasting for at least 3 months to ensure clinical stability |
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| E.1.1.1 | Medical condition in easily understood language |
| Peripheral arterial occlusive disease and intermittent claudication |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10074576 |
| E.1.2 | Term | Peripheral arterial occlusive disease Fontaine stage IIb |
| E.1.2 | System Organ Class | 100000004866 |
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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 |
The study is conducted to assess the efficacy and safety of nitroglycerin in a scheduled forced titration design of sublingual GTN. In order to avoid adverse reactions like e.g. headaches, the dosing regimen comprises a low initial dose with weekly increments to a sub-chronic target dose of sublingual nitroglycerin on walking distance in PAOD-patients with femoro-popliteal stenosis and intermittent claudication (stage II) relative to placebo. Primary Objectives are:
1) Showing improvement in initial walking distance (ICD) according to a treadmill protocol with constant workload (3.2 km/h and 12% grade).
2) Showing improvement in walking distance: Absolute claudication distance (ACD) according to a treadmill protocol with constant workload (3.2 km/h and 12% grade).
The study is a proof of concept study. |
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| E.2.2 | Secondary objectives of the trial |
1) Frequency and intensity of adverse events (AE), blood pressure/heart rate, in particular: headache, hypotension/orthostasis (dizziness, lightheadedness, syncope/presyncope)
2) Changes in the ankle-brachial-index (ABI)
3) Assessment of adverse events
4) Changes in patient´s quality of life
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|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Male or female outpatients, aged ≥ 18 years
2) Ability to exercise a treadmill test
3) Confirmation of clinical diagnosis of PAOD as objective evidence of Fontaine stage IIb PAOD i.e.:
a) reduced ankle systolic blood pressure (ABI <0.9) on target leg,
b) walking distance < 200 m in standardized walking test (initial claudication distance (ICD))
4) Completion of at least two treadmill tests within a time interval of ≥ 1 week, the maximum change in claudication distance should not exceed a predefined threshold of 25% for the absolute claudication distance (ACD).
5) Intermittent claudication lasting for at least 3 months
6) Stable smoking habits for at least 3-6 months prior to inclusion
7) Signed Informed Consent
|
|
| E.4 | Principal exclusion criteria |
1. Asymptomatic PAOD Patients, equivalent to PAOD Fontaine stage I
2. PAOD-patients with critical limb ischemia (CLI), equivalent to EMA´s or Fontaine´s PAOD-stages III and IV
3. Any kind of revascularization (endovascular, surgical) in the iliac and/or leg arteries within 3 months prior to Visit 1
4. Current unstable angina
5. History of congestive heart failure, NYHA class III or IV
6. Use of confounding medications within the last 4 weeks prior to Visit 1 – e.g. vasoactive compounds like Cilostazol or Naftidrofuryl
7. Patients with significant disease of the cardiac valves or symptomatic untreated arrhythmias
8. Other diseases limiting exercise capacity (angina pectoris, heart failure, respiratory diseases, orthopedic diseases, neurological disorders)
9. Uncontrolled hypertension (> 180/100mmHg) or hypotension (supine SBP <100 mmHg). Whether 24-hour or ambulatory blood pressure monitoring is applied will be at the discretion of the investigator.
10. Severe anaemia
11. Anamnestically known type I or II diabetes mellitus
12. Anamnestically known increased intracranial pressure
13. Anamnestically known glaucoma
14. Subjects with any clinically relevant laboratory abnormality (assessed by the investigator)
The following limits for relevant laboratory abnormality are set in particular:
o calculated glomerular filtration rate (GFR) < 30 mL/min/1.73 m2
o haemoglobin < 10 g/dl
o serum liver enzymes (ASAT, ALAT, GGT) > 3x upper range of normality
15. Know hypersensitivity to any ingredient in the product formulation
16. Pregnancy or lactation period
17. Women of childbearing potential without an effective contraceptive method
18. Planned surgical intervention requiring hospitalization during the clinical trial
19. Previous inclusion in the present clinical trial or parallel participation in another clinical trial (up to 8 weeks before Visit 1)
20. Incapability of understanding nature, meaning and consequences of the clinical trial
21. Patient unable to read and / or write
22. Patients in custody by juridical or official order
23. Patients, who are members of the staff of the trial center, staff of the sponsor or involved
24. Clinical Research Organizations (CROs), the investigator him- / herself or close relatives of the investigator
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| One primary endpoint is defined as the increase in “walking distance” measured as initial claudication distance (ICD) at Visit 7 (end of treatment period) compared to baseline. A further primary endpoint is the walking distance by absolute claudication distance (ACD) at Visit 7 (end of treatment period) compared to baseline. For both primary endpoints a constant workload treadmill protocol is used (3.2 km/h and 12% grade). The relationship between worktime and workload follows a linear function. The justification for the selection of both primary endpoints is based on a recommendation by the EMA and according to extensive discussions with specialists in angiology. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
At Visit 7 = after 12 weeks of treatment.
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| E.5.2 | Secondary end point(s) |
1. Walking distance by initial claudication distance (ICD) at Visit 8 and Visit 9 (both during follow-up phase) will be tested for superiority analogously to the respective primary endpoint. A constant workload treadmill protocol is used (3.2 km/h and 12% grade).
2. Walking distance by absolute claudication distance (ACD) at Visit 8 and Visit 9 (both during follow-up phase) will be tested for superiority analogously to the respective primary endpoint. A constant workload treadmill protocol is used (3.2 km/h and 12% grade).
3. Ankle-brachial-index (ABI): Changes of ABI during the treatment course at Visit 7, 8 and 9 and in comparison to Visit 2 (baseline) will be analyzed by MMRM analysis of covariance using ABI differences from baseline as dependent variable, baseline ABI as covariate, visit (repeated), treatment and center as fixed effects. The treatment effect of ABI at Visit 7, Visit 8 and Visit 9 will be calculated from the model.
4. The following Questionnaires
a. EQ-5D
b. ICQ
will be analysed at Visit 7 and 9 and in comparison to Visit 2 (baseline) by MMRM analysis of covariance using differences of the respective score from baseline as dependent variable, baseline score as covariate, visit (repeated), treatment and center as fixed effects. The treatment effects of ED-5D and ICQ at Visit 7, Visit 8 and Visit 9 will be calculated from the model.
5. Adverse events: The MedDRA system will be used to code adverse events. AEs (preferred terms) will be tabulated for each treatment group by system organ class according to MedDRA. The tables will divide the AEs into the defined categories of severity and investigator’s causality assessments. AEs will also be displayed according to time of onset (within treatment period and after treatment), actions taken, pattern of occurrence and outcome. This basic display of AEs will be used to compare the AE rates between treatment groups
6. Adverse drug reactions (ADR): The assessment of adverse drug reactions (ADR), the following parameter will be evaluated:
i. The percentage of patients with at least one reported ADR will be compared between treatment groups using the Fisher’s exact test
ii. The percentage of patients discontinued due to ADR/special AE will be compared between treatment groups using the Fisher’s exact test
7. Special AEs, i.e. headache, hypotension/orthostasis (dizziness, lightheadedness, syncope/ presyncope): The assessment of special AEs, the following parameter will be evaluated:
i. The percentage of patients with at least one reported special AE will be compared between treatment groups using the Fisher’s exact test
ii. The percentage of patients discontinued due to special AE will be compared between treatment groups using the Fisher’s exact test
8. Serious adverse events (SAE): Percentage of patients having experienced at least one SAE during the clinical trial period will be analysed descriptively by Fishers exact test. In addition, these events will be listed individually and judged medically in order to evaluate the comparability of the safety profile of both treatment groups regarding all SAEs.
9. Vital signs will be described for each visit separately by treatment using descriptive statistics.
10. Investigator’s and patient´s global judgement of tolerability [score] will be displayed by frequency and percentages will be analyzed by the Wilcoxon test adjusted for centers (van Elteren test).
11. Laboratory data will be presented by means of shift tables displaying the numbers of patients switching from baseline (= Visit 1) to end of treatment visit (= Visit 7) between the categories “above normal range”, “within normal range”, and “below normal range”. Descriptive statistics will also be presented for measured values and for changes from baseline. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary endpoints related to efficacy will be assessed at visit 7, visit 8 and visit 9.
Scondary enpoints related to safety will be evaluated starting after visit 2 throughout the whole Trial. |
|
| 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 | No |
| 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) | 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) | 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 | 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) | No |
| E.8.2.2 | Placebo | Yes |
| 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 | 12 |
| 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
|
| End of the trial is defined as final study report available. This is planned to be within one year after last patient last visit. |
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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 | 11 |
| E.8.9.1 | In the Member State concerned days | |
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