| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderate to severe primary axillary hyperhidrosis |
|
| E.1.1.1 | Medical condition in easily understood language |
| Primary axillary hyperhidrosis is a dermatologic and neurologic disorder that is chronic and distressing and involves the increased production of sweat. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Skin and Connective Tissue Diseases [C17] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10020642 |
| E.1.2 | Term | Hyperhidrosis |
| E.1.2 | System Organ Class | 10040785 - Skin and subcutaneous tissue disorders |
|
| 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 assessment of efficacy and safety of topical administration of 1% GPB or placebo cream in patients with primary axillary hyperhidrosis and the assessment of long-term efficacy and safety of topical administration of 1% GPB cream in patients with primary axillary hyperhidrosis. |
|
| E.2.2 | Secondary objectives of the trial |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Diagnosis of severe primary axillary hyperhidrosis with a HDSS score of 3 or 4;
2. At least 50 mg of sweat production in each axilla measured gravimetrically at room temperature and at a humidity consistent with the normal climate in that area over a period of 5 minutes (patients should have acclimatized to that room for at least 30 minutes);
3. Men and women aged 18 to 65 years at the time of informed consent with a body mass index of 18-32 kg/m²;
4. Corrected QT (QTc) ≤450 msec, or QTc <480 msec in patients with bundle branch block;
5. Female patients of childbearing potential must have a negative pregnancy test at Screening;
6. Female patients of childbearing potential must use (for a least 3 monthly cycles before the first dose, during the study, and 1 cycle after the last dose of the IMP) a highly effective method of contraception or birth control (failure rate less than 1% per year when used consistently and correctly) and should be informed of the potential risks associated with becoming pregnant while enrolled in this clinical investigation. Reliable methods for this study are: combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable), intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, sexual abstinence or vasectomized sexual partner. Abstinence is only accepted as true abstinence when this is in line with the preferred and usual lifestyle of the patient (periodic abstinence [e.g. calendar, ovulation, symptothermal, post-ovulation methods and withdrawal] is not an acceptable method of contraception). Postmenopausal (no menses for at least 1 year without alternative medical cause) or surgically sterile female patients (tubal ligation, hysterectomy or bilateral oophorectomy) may be enrolled.
7. Able to comply with protocol requirements, including blood sample collection;
8. The patient is capable of understanding the nature, significance and implications of the clinical trial and to form a rational intention in the light of the facts, voluntarily agrees to participation and the study’s provisions and has duly signed the informed consent form;
9. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <2 x upper limit of normal (ULN), alkaline phosphatase (AP) and bilirubin ≤1.5 x ULN at Screening (free bilirubin ≥1.5 × ULN will not directly lead to study discontinuation if bilirubin fraction test result of direct bilirubin <35% is available). |
|
| E.4 | Principal exclusion criteria |
1. Known allergy to any of the components in the investigational product;
2. Hypersensitivity against glycopyrrolate;
3. Secondary hyperhidrosis, e.g. hyperhidrosis that is secondary to other underlying diseases including hyperthyroidism, lymphoma, malaria and climacteric hyperhidrosis;
4. Previous surgical treatment of hyperhidrosis including sympathectomy, surgical debulking of the sweat glands, subcutaneous tissue curettage and ultrasonic surgery;
5. Botulinum toxin treatment for the treatment of axillary hyperhidrosis in the previous 4 months;
6. Presence or history of neuromuscular disease;
7. Angle closure glaucoma or its precipitation (narrow angle);
8. Mycotic, other skin infections and other dermal disorder including infection at anticipated application sites in either axilla;
9. Significant cardiovascular disease, thyrotoxicosis and men with a history of urinary retention requiring catheterization due to prostatic hypertrophy or severe obstructive symptoms of prostatic hypertrophy;
10. Significant cardiac arrhythmia such as tachycardiac atrial fibrillation and very frequent extrasystoles;
11. Patients with uncontrolled diabetes mellitus;
12. Patients with severe renal impairment (including Gilbert’s syndrome);
13. Patients with active or clinical history of asthma (within the last 10 years) or chronic bronchitis;
14. Patients with a history of ileus, gastrointestinal stenosis, pronounced chronic inflammatory bowel disease, toxic megacolon;
15. Patients with epilepsy;
16. Women who are pregnant, lactating, possibly pregnant or planning a pregnancy during the study period;
17. Use of prohibited medication or treatment (see Section 11.2.1);
18. Use of investigational drugs within 30 days or 5 half-lives (whichever is longer) or participation in another clinical trial within 30 days prior to the planned first dosing;
19. Psychiatry disorder or cognitive disorder that may affect the patient's ability to give informed consent or to follow specified study procedures;
20. Positive serology test for hepatitis B or C virus, or human immunodeficiency virus 1 or 2;
21. History of alcohol or drug abuse within the last 3 years;
22. Any condition or situation that, in the investigator's or sub-investigator's opinion, may interfere with the patient's participation in the study;
23. Employees of the sponsor or sponsor’s representative; employees or relatives of the investigator;
24. Patients who are detained officially or legally to an official institute or those that have been committed to an institution by an order issued either by the judicial or the administrative authorities;
25. Any score higher than 1 (i.e. 2 or 3) in the neurological examination.;
26. Patients with myasthenia gravis;
27. Patients under treatment with potassium chloride;
28. Patients with a disturbed blood-brain-barrier (such as patients with recent [within 1 year of Screening] craniocerebral trauma, chemotherapy, radiation therapy, or skull opening surgeries, or recent intravenous drug users);
29. Patients with psoriasis inversa or psoriasis pustulosa generalisata. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary endpoints:
Dose-confirming part (Phase 3a):
1. Absolute change in sweat production assessed by gravimetric measurement (GM) from Baseline (Day 1a) to Day 29 in the 1% GPB group compared with the placebo group.
Long-term part (Phase 3b)(only for newly recruited patients):
2. Absolute change in sweat production assessed by GM from Baseline (Day 1b) to Week 12. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Dose-confirming part (Phase 3a):
1. Screening Visit, Baseline (Day 1a), Day 29.
Long-term part (Phase 3b)(only for newly recruited patients):
2. Screening Visit, Baseline (Day 1b), Week 4, Week 12. |
|
| E.5.2 | Secondary end point(s) |
Secondary endpoints:
Efficacy
Dose-confirming part:
Key secondary endpoints
1. Percentage of responders assessed by the HDSS (≥2-point improvement from Baseline) on Day 29 in the 1% GPB group compared with the placebo group;
2. Absolute change in the hyperhidrosis quality of life (HidroQOL) questionnaire from Baseline to Day 29 in the 1% GPB group compared with the placebo group.
Further secondary endpoints
3. Absolute change in sweat production assessed by GM from Baseline (Day 1a) to Day 29 by treatment group;
4. Percentage change in sweat production assessed by GM from Baseline to Day 29 by treatment group and in the 1% GPB group compared with the placebo group;
5. Percentage of responders assessed by GM at Day 29 (defined by sweat reduction of ≥50%, ≥75%, and ≥90% compared with Baseline) in the 1% GPB group compared with the placebo group;
6. Absolute change in the HDSS from Baseline to Day 29 by treatment group and in the 1% GPB group compared with the placebo group;
7. Absolute change in the HDSS from Baseline to Day 15 by treatment group and in the 1% GPB group compared with the placebo group;
8. Percentage of responders assessed by the HDSS (≥2-point improvement from Baseline) on Day 15 in the 1% GPB group compared with the placebo group;
9. Absolute change in the HidroQOL questionnaire from Baseline to Day 15 by treatment group and in the 1% GPB group compared with the placebo group;
10. Absolute change in the HidroQOL questionnaire from Baseline to Day 29 by treatment group;
11. Absolute change in the dermatology life quality index (DLQI) questionnaire from Baseline to Day 15 by treatment group and in the 1% GPB group compared with the placebo group;
12. Absolute change in the DLQI questionnaire from Baseline to Day 29 by treatment group and in the 1% GPB group compared with the placebo group.
Long-term part:
Key secondary endpoints
13. Percentage of responders assessed by the HDSS (≥2-point improvement from Baseline) at Week 12;
14. Percentage of responders assessed by the HDSS (≥2-point improvement from Baseline) at Week 28;
15. Absolute change in the HidroQOL questionnaire from Baseline to Week 12.
Further secondary endpoints
16. Percentage change in sweat production assessed by GM from Baseline to Week 4 and Week 12; (Only for patients newly recruited to the long-term part.)
17. Absolute change in sweat production assessed by GM from Baseline to Week 4; (Only for patients newly recruited to the long-term part.)
18. Percentage of responders assessed by GM at Week 4 and Week 12 (defined by sweat reduction of ≥50%, ≥75%, and ≥90% compared with Baseline); (Only for patients newly recruited to the long-term part.)
19. Percentage of responders assessed by the HDSS (≥2-point improvement from Baseline) at Weeks 4, 8, 52, and 72;
20. Absolute change in the HDSS from Baseline to Weeks 4, 8, 12, 28, 52, and 72;
21. Absolute change in patient-rated hyperhidrosis severity from Baseline to Weeks 4, 8, 28, 52, and 72;
22. Absolute change in the HidroQOL questionnaire from Baseline to Weeks 4, 8, 28, 52, and 72;
23. Absolute change in the DLQI questionnaire from Baseline to Weeks 4, 8, 12, 28, 52, and 72.
Safety and tolerability
Dose-confirming part:
24. Frequency, severity, and relation of AEs, SAEs, treatment-emergent AEs (TEAEs), suspected unexpected serious adverse reactions (SUSARs),
and discontinuations due to AEs;
25. Local tolerability at the application site assessed by the investigator using a skin reaction score;
26. Vital signs (heart rate, blood pressure, and body temperature);
27. 12-lead electrocardiogram (ECG);
28. Neurological examination.;
29. Safety laboratory (hematology, chemistry, and urinalysis).
Long-term part:
Up to and including Week 12
30. Frequency, severity, and relation of AEs, SAEs, TEAEs, SUSARs, and discontinuations due to AEs;
31. Local tolerability at the application site assessed by the investigator using a skin reaction score;
32. Neurological examination;
33. Safety laboratory (hematology, chemistry, and urinalysis);
34. Product use per month.
Week 13 to Week 72/EOTb
35. Frequency, severity, and relation of AEs, SAEs, TEAEs, SUSARs, and discontinuations due to AEs;
36. Local tolerability at the application site assessed by the investigator using a skin reaction score;
37. Vital signs (heart rate, blood pressure, and body temperature);
38. 12-lead ECG;
39. Neurological examination;
40. Safety laboratory (hematology, chemistry, and urinalysis);
41. Product use per month.
Week 72 to 76
42. Frequency, severity, and relation of AEs, SAEs, TEAEs, SUSARs, and discontinuations due to AEs;
43. Local tolerability at the application site assessed by the investigator using a skin reaction score. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.Screening, Baseline, Day 15, D29
2.SC, BL, D15, D29
3.SC, BL, D29
4.SC, BL, D29
5.SC, BL, D29
6.SC, BL, D15, D29
7.SC, BL, D15
8.SC, BL, D15
9.SC, BL, D15
10.SC, BL, D15, D29
11.BL, D15
12.BL, D15, D29
13.SC, BL, Week 4, W8, W12
14.SC, BL, W4, W8, W12, W28
15.SC, BL, W4, W8, W12
16.SC, BL, W4, W12
17.SC, BL, W4
18.SC, BL, W4, W12
19.SC, BL, W4, W8, W12, W28, W52, W72
20.SC, BL, W4, W8, W12, W28, W52, W72
21.BL, W4, W8, W12, W28, W52, W72
22.SC, BL, W4, W8, W12, W28, W52, W72
23.BL, W4, W8, W12, W28, W52, W72
24.SC to D29
25.BL to D29
26.SC, D29
27.SC, D29
28.SC to D29
29.SC to D29
30.SCR to W12
31.BL to W12
32.SC to W12
33.BL to W12
34.BL to W12
35.W12 to W72
36.W12 to W72
37.W28, W72
38.W72
39.W72
40.W72
41.W12 to W72
42.W72 to W76
43.W72 to W76 |
|
| 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) | 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 | Yes |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Dose-confirming Phase 3a: randomised, double-blind, parallel group; Long-term Phase 3b: open. |
|
| 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
| 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 | 40 |
| 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 | 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
|
| The end of the study is defined as the date of the data base lock for the final analysis, at the latest 3 months after the last visit of the last patient in the long-term part of the study. |
|
| 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 | 6 |
| 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 | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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