REDUCING SIDE EFFECTS OF SHORT ACTING NO DONORS

Abstract

The present invention pertains to a short acting NO donor for use in a method of reducing side effects of a treatment with said short acting NO donor, comprising administering during a defined time period a gradually increasing amount of said short acting NO donor in an intermitting manner. The present invention is further directed to a short acting NO donor for use in a method for the prevention or treatment of an arterial insufficiency, wherein the NO donor is administered in an intermitting manner, and wherein during the initial phase of the administration, the amount of said short acting NO donor is gradually increased.

Claims

1. A method of reducing side effects of a treatment with a short acting NO donor, comprising administering the short acting NO donor during a defined time period, wherein a gradually increasing amount of said short acting NO donor is administered in an intermitting manner.

2. The method according to claim 1, wherein the defined time period is an initial phase of the treatment with the short acting NO donor.

3. The method according to claim 1, wherein said defined time period is 3 days to 40 weeks long, preferably 1 week to 16 weeks long, more preferably 3 to 4 weeks long, and most preferred at least two weeks long.

4. The method according to claim 1, wherein an initial amount of the short acting NO donor administered during the defined time period is a subtherapeutical or less effective amount.

5. The method according to claim 1, wherein a final amount of the short acting NO donor administered during the defined time period is a therapeutically active amount.

6. The method according to claim 1, wherein the NO donor is administered at least once a day, preferably up to 2 to 3 times a day, more preferably up to 4 times a day.

7. The method according to claim 1, wherein the NO donor is administered lingually, sublingually, inhalatively, buccally, transmucosally or oromucosally.

8. The method according to claim 1, wherein said treatment is for the treatment or prevention of an arterial insufficiency.

9. The method according to claim 8, wherein the short acting NO donor is administered in a final amount effective for the induction of arteriogenesis.

10. The method according to claim 1, wherein the short-acting NO donor is selected from octyl nitrite, amyl nitrite, nitroglycerin, isosorbide dinitrate, isoididmononitrat, isoididdinitrat, mannitol hexanitrate.

11. The method according to any claim 1, wherein the short acting NO donor is administered in form of a powder, granules, a tablet, a capsule, a liquid, a gel, a solution or an aerosol.

12. The method according to claim 11, wherein the NO donor is administered by means of a dosage form delivering a uniform dose, preferably in form of a stick pack, a tablet, a capsule, a (pre-)metered spray, a (pre-) metered inhaler, a (pre-)metered delivery device, or, alternatively, by means of a dosage form delivering an adjustable dose, preferably in form of an adjustable metering device.

13. A short acting NO donor for use in a method for the prevention or treatment of an arterial insufficiency, wherein a short acting NO donor is administered in an intermitting manner, and wherein during an initial phase of the administration, the amount of said short acting NO donor is gradually increased.

14. The method according to claim 13, wherein the initial phase is 3 days to 40 weeks long, preferably 1 week to 16 weeks long, more preferably 3 to 4 weeks long, and most preferred at least two weeks long.

15. The method according to claim 13, wherein an initial amount of the short acting NO donor is administered during the initial phase of the administration, wherein donor this initial amount is a subtherapeutical or less effective amount.

16. The method according to claim 13, wherein a final amount of the administered short acting NO donor is a therapeutically active amount.

17. The method according to claim 13, wherein the short acting NO donor is administered at least once a day, preferably up to 2 to 3 times a day, more preferably up to 4 times a day.

18. The method according to claim 13, wherein the short acting NO donor is administered lingually, sublingually, inhalatively, buccally, transmucosally or oromucosally.

19. The method according to claim 13, wherein the short acting NO donor is selected from octyl nitrite, amyl nitrite, nitroglycerin, isosorbide dinitrate, isoididmononitrat, isoididdinitrat, mannitol hexanitrate.

20. The method according to claim 13, wherein the short acting NO donor is administered by means of a dosage form delivering a uniform dose, preferably in form of a stick pack, a tablet, a capsule, a (pre-)metered spray, a (pre-)metered inhaler, a (pre-) metered delivery device, or, alternatively, by means of a dosage form delivering an adjustable dose, preferably in form of an adjustable metering device.

Description

FIGURE LEGENDS

[0168] FIG. 1: Schematic representation of the multi-centre, randomized, placebo-controlled, double-blind trial to assess the efficacy and safety of nitroglycerin sublingual powder on the walking distance in a scheduled forced titration design in patients with peripheral artery occlusive disease (PAOD) and intermittent claudication (EUDRA-CT 2016-004460-19) (Example 3).

[0169] FIG. 2: Interim analysis of headache incidence in a multi-centre placebo-controlled, double-blind trial to assess the efficacy and safety of nitroglycerin sublingual powder on the walking distance in a scheduled forced titration design in patients with peripheral artery occlusive disease (PAOD) and intermittent claudication after finalized 3 week titration and first week of regular treatment (Example 3).

EXAMPLES

Example 1

[0170] A 35-year old men who is known to show severe headache when taking sublingual nitroglycerin in a therapeutic dose was put on a less effective amount of approximately 0.15 mg GTN TID (morning, noon, evening) sublingual powder to start. At this dosage he had no headache or other known GTN side effects. After a week he increased the dose to 0.3 mg GTN, after the second week to 0.5 mg, after another week he reached the final dosage of 0.7 mg without side effects.

Example 2

[0171] A 51-year old woman who responded with nausea and mild headache to an initial dose of 0.4 mg sublingual nitroglycerin was put on 0.15 mg TID (morning, noon, evening) to start. At this dosage she had no nausea or headache or other known GTN side effects. After a week, she increased the dose to 0.3 mg GTN TID, after the second week she reached the final dosage of 0.4 mg TID without side effects.

Example 3

[0172] In a multi-centre, randomized, placebo-controlled, double-blind trial the efficacy and safety of nitroglycerin sublingual powder on the walking distance in a scheduled forced titration design in patients with peripheral arterial occlusive disease (PAOD) and intermittent claudication is assessed (EUDRA-CT 2016-004460-19). This clinical Phase IIa proof-of-concept study with 50 patients suffering from peripheral artery disease (PAD) and a pain free walking distance <200 metres (stadium Fontaine IIb) investigates the efficacy of an intermittent administration of nitroglycerin on the walking distance via the induction of arteriogenesis and consists of a 12-week phase of drug administration and a 12-week follow up phase without drug administration. In order to reduce the expected side effects of the short acting NO donor administration the study does not start with the therapeutic dose but follows a forced titration with two titration steps as described in the following. Drug administration starts with a low initial dose of 0.3 mg nitroglycerin for one week, followed by 0.5 mg (titration step 1) for another week. From the third week on the patients receive the final therapeutically active dosage of 0.7 mg nitroglycerin (titration step 2) for another ten weeks (FIG. 1). The patients are advised to take the dosages in the morning, noon and evening so that the short acting NO donor is administered in an intermittent manner.

[0173] Study parameters are pain free walking distance (ICD=initial claudication distance) and maximum walking distance (ACD=absolute claudication distance) assessed by treadmill walking tests. These parameters are commonly accepted parameters in studies investigating the efficacy of therapies regarding peripheral artery disease. These parameters are the primary and secondary endpoints. Therefore for both parameters the increase in walking distance is measured. For the primary endpoint the difference from the walking distances of treadmill tests performed before the start of the drug administration phase (baseline) to week 12 (at the end of drug administration phase) is calculated.

[0174] For the secondary endpoint the difference of the walking distances of treadmill test performed before the start of the drug administration phase (baseline) to 6 weeks after the drug administration phase (first follow up visit at week 19-20) and to the end of the 12-week follow up phase (second follow up visit at week 26) is measured.

[0175] Additional secondary parameters are ankle-brachial index (ABI, difference from baseline to week 12, to week 19-20 and to week 26), questionnaires EQ-5D and ICQ (difference from baseline to week 12 and 19-20) and Oxygen saturation (SpO.sub.2 before start of drug administration phase, at the start of the drug administration phase, at the end of the 12-week drug administration phase, 6 weeks after drugs administration phase and at the end of the 12-week follow up phase).

[0176] Participants report adverse effects during the study with headache being one of the adverse effects.

Interim Analysis of the Ongoing Study

[0177] The study has not yet been finalized but an interim analysis regarding headache as an adverse effect of the study drug has been performed (FIG. 2, Table 1-3).

[0178] At the time point of the interim analysis the study was still blinded, so with regard to patients' reported adverse event headache it could not be distinguished between the frequency of headache in the verum and the placebo group.

[0179] As the titration of the study medication takes place in the first 3 weeks, the analysis is focused on reported headache in the first three weeks plus in week 4 to also monitor possible late or ongoing side effects.

[0180] The analysis includes 35 participants so far which are at different time points of the study protocol. In FIG. 1 the individual headache days of the 35 participants are shown. Some participants have already reached the end of the 12-week treatment period and are in the follow-up period, some participants are still on treatment, but all participants (33) have surpassed the titration phase and are on the final dosage of 0.7 mg GTN.

TABLE-US-00001 TABLE 1 Number of participants and the number of weekly and total study days. Number of participants 35 Number of study days 245 per week (35 7) Number of study days 980 (week 1-4) (35 7 4) Number of study days total 2940 (drug administration phase) (35 7 12) Number of drop-out days 487 (drug administration phase) and not completed days of patients on treatment Number of study days 2453 corrected by drop-out days (drug administration phase) and not completed days of patients on treatment Number of drop-out days 53 (week 1-4 drug administration phase) Number of study days 927 corrected by drop-out days (week 1-4 drug administration phase)

TABLE-US-00002 TABLE 2 Number and percentage of participants with and without headache in the first 4 weeks on a weekly basis. Week 1 2 3 4 Dosage (GTN) 0.3 mg 0.5 mg 0.7 mg 0.7 mg Participants with 10 7 5 3 headache (n) Headache (%) 28.6 20.0 14.3 8.6 Study days (n) 245 245 245 245 Drop-out days (n) 0 7 18 28 Study days corrected by 245 238 227 217 drop-out days (n) Headache days (n) 38 31 29 21 Headache days (%) 15.5 13.0 12.3 9.7

[0181] The number of participants with headache is subsequently reduced from n=10 in week 1 over n=7 in week 2 to n=5 in week 3 and n=3 in week 4.

[0182] Referring to the 35 participants this represents 28.6% of the participants in week 1. This initial percentage is reduced subsequently to 20% in the second week, 14.3% in the third and 8.6% in the fourth week.

[0183] Of the 35 participants 6 participants had headache on a single day in the first 4 weeks, but not during the first three days. 6 different participants had headache that lasted more than one day, in 5 of these the headache lasted more than a week.

[0184] Of the 927 study days (number of study days corrected by drop-out days in week 1-4 of the drug administration phase) during the first 4 weeks of the trial the participants had headache on 118 days which is an overall percentage of 12.7% with 15.5% in week 1, 13.0% in week 2, 12.3% in week 3 and 9.7% in week 4.

[0185] 245 participant headache days were recorded for a total of 2453 study days so far, which amounts to 10%.

[0186] 209 headache days (85% of the total 245 headache days) were recorded for 3 participants that continuously had headache in the first 4 weeks and in the further course of the study.

[0187] There was one possibly headache related drop-out recorded during the titration in the first 4 weeks. In the further course of the therapy 2 additional participants dropped out due to headache.

CONCLUSION

[0188] Due to the provisional character of the interim analysis it is not clear how an unblinding of the study data will influence the study outcome with regard to the side effect headache.

[0189] On basis of literature data an overall headache frequency of below 30% in the present study can be considered as low. During the therapy with short acting NO donors such as nitroglycerin or ISDN, headache is reported to be generally a very common side effect with a reported frequency of up to 64% when short acting NO donors are administered for therapeutical means.

[0190] In the present study it was found that the overall headache frequency started on a low 28.6% in the first week and was subsequently reduced during the titration period to 8.6% in week 4. This is a low frequency in comparison to the reported rate of headache in the literature for sublingual nitroglycerin.

[0191] The percentage of headache as well as the intensity of headache during the therapy with nitrates is known to be dose-dependent. Therefore higher doses are expected to trigger a higher number of side effects. Without titration a dosage of 0.7 mg GTN is to be expected to generate more side effects than a dosage of 0.3 mg GTN.

[0192] In contrast thereto the present study did not monitor an increased headache frequency in week 2, 3 or 4 as a result of the increased dosage. Therefore the study results may confirm that the titration regime prevents a dose related increase of headache as a side effect, although it could not be distinguished between the frequency of headache in the verum and the placebo group due to the blinded data.

[0193] The adjustment process under a titration regime is expected to need some days, so that headaches in the first days of the overall titration period or the first days after each titration step might to be expected more frequent than in the following days or weeks. The titration starting dose (0.3 mg GTN) in this trial is significantly lower than the final therapeutic dosage (0.7 mg GTN) to smoothen the adjustment process. There are only 5 participants (14.3%) that have headache during the first days of treatment which is considered a lower percentage than expected without titration and a start with the therapeutical dose of 0.7 mg GTN.

Limitations of the Interim Analysis and/or the Trial in Respect of the Side Effect Headache

[0194] It is known, that irrespective of the type of clinical study and investigated drugs headache is a common side effect due to the high frequency in which spontaneous headache occurs in the population. In a study covering a period of twelve weeks spontaneous headache is to be expected besides drug-induced side effects. So, single headache days in the course of the study may be spontaneous headache and not necessarily drug-induced.

[0195] Therefore, it is anticipated that beside GTN-induced headache also spontaneous headache will be reported during the study in the verum as well as in the placebo group. This will probably influence the final number of drug-induced headaches.

[0196] In the present trial a history of chronic headache or migraine was no exclusion criterion. So there might be a fraction of the trial participants with a history of chronic headache or migraine. Chronic headache or migraine may have led to an overestimation of headache frequency as three participants had continuous headache during the complete study (resp. until drop-out).

[0197] 3 participants with possible chronic headache or migraine background account for 65% of the headache days in the first 4 weeks (82 out of 127 headache days) and 85% of the headache days (212 out of 251 headache days) in the overall study.

TABLE-US-00003 TABLE 3 Results with participants with possible chronic headache or migraine background excluded. Week 1 2 3 4 Participants with Headache 10 7 5 3 (n) Participants with possible 3 3 3 3 chronic headache or migraine history Participants with headache 7 4 2 0 corrected by participants with possible chronic headache or migraine history (n) Headache corrected by 20 11.4 5.7 0 participants with possible chronic headache or migraine history (%) Participants headache days 19 10 7 0 corrected by participants with possible chronic headache or migraine history (n) Participant headache days 7.8 4.2 3.1 0 corrected by participants with possible chronic headache or migraine history (%)

[0198] When excluding the 3 trial participants due to their possible background of chronic headache or migraine from the data analysis the percentage of participants (and participant days) with headache is even lower. The remaining participants with headache would then amount to only 15% of participant headache days and only 20% of participants with headache in the first week. Titration reduces them to 11.4% in week 2 and 5.7% in week 3. In week 4 no participant (0%) (except the 3 suspected chronic headache or migraine participants) complained of headache as a side effect. This trend continued in weeks 5-12.

[0199] So far there has only been one participant drop-out likely due to headache in the titration phase, in 2 later drop-outs headache may have been the underlying cause. These dropped out participants may have a potential chronic headache or migraine background.

Expected Final Study Results

[0200] The study is planned to be finalized in 2019.

[0201] After the study is finalised and the data have been unblinded, we expect to find a lower frequency of headache in the titration verum group than reported for untitrated short acting nitrates use in literature data.

[0202] We expect the titration to reduce the side effect headache within the first three weeks to a low level or even prevent them completely despite the increasing dosage of nitroglycerin.

[0203] We also expect a low number of drop-outs during the beginning of the trial therapy, which is normally the most critical time in a trial as well as in real life therapeutic regimen.