| 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] - Nervous System Diseases [C10] |
| 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 | 10027599 |
| E.1.2 | Term | Migraine |
| E.1.2 | System Organ Class | 10029205 - Nervous system 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 |
Primary Objectives
1. To assess pruritus and rash after administration of Neublastin or placebo in healthy subjects and migraine patients (Parts A and B)
2. To assess headache and other migraine-associated symptoms after administration of Neublastin or placebo in migraine patients (Part B)
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| E.2.2 | Secondary objectives of the trial |
Secondary Objectives
1. To assess Neublastin-induced mechanical and thermal sensory responses using nociceptive thresholds in healthy subjects and migraine patients (Parts A and B)
2. To assess headache and other migraine-associated symptoms in healthy subjects upon administration of Neublastin or placebo (Part A)
3. To assess changes in temperature perception upon administration of Neublastin or placebo in healthy subjects and migraine patients (Parts A and B)
4. To characterize the pharmacokinetics (PK) profile of a single IV dose of Neublastin in healthy subjects and in migraine patients (Parts A and B)
5. To characterize the safety and tolerability of a single IV dose of Neublastin in healthy subjects and in migraine patients (Parts A and B)
6. To characterize the safety and tolerability of Neublastin administered intradermally (ID) in healthy subjects (Part A)
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female from 18 to 65 years of age (inclusive) at screening visit.
3. Body mass index (BMI) between 18 and 35 kg/m2, inclusive at screening, with a minimum weight of 50 kg at screening.
4. Subject is judged by the investigator to be in good health based on medical history (except for migraine in patients participating in Part B) based on all available data prior to administration of initial dose of study drug.
7. Able and willing to provide signed informed consent prior to any study-mandated procedure.
Additional inclusion criteria Part B (episodic migraine patients):
9. History of episodic migraine headaches with or without aura for ≥6 months as determined by a diagnosis provided by a neurologist.
10. Migraine headaches should either fulfil criteria A and B for migraine without aura or criterion C (“Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition,” 2018).
A. Headache has at least 2 of the following characteristics:
• unilateral location
• pulsating quality
• moderate or severe pain intensity (≥4 on headache questionnaire)
• aggravation by or causing avoidance of routine physical activity
B. Experiences at least 1 of the following during headache:
• nausea and/or vomiting
• photophobia and phonophobia
C. Headache described as mimicking usual migraine attack treated and responsive to treatment with triptan.
11. Migraine frequency: 1 to 7 migraine days per month in each of the 3 months prior to screening.
12. Migraine headaches should be responsive to treatment with non-steroidal anti-inflammatory agents (NSAIDs) and/or triptans.
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| E.4 | Principal exclusion criteria |
1. History of clinically significant cardiovascular, immunological, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, dermatologic, neurological (except for migraine for patients in Part B) or psychiatric disease, as assessed by the investigator that may confound the results of the study or pose an additional risk to the subject by participation in the study.
2. History of arterial or venous thrombotic or thromboembolic disease.
3. History of stroke or transient ischemic attack.
5. Recent history (within 1 year prior to screening) or presence of a clinically significant chronically painful condition or recent and unresolved acutely painful condition, except for migraine in Part B.
6. History of drug or alcohol abuse (>14 units of alcohol per week) within a year prior to the screening visit.
11. Use of anti-platelet or anti-coagulation therapy, including but not limited to daily aspirin (except for 81 mg daily doses), clopidogrel, prasugrel, ticagrelor, enoxaparin, apixaban, warfarin.
14. Presence of HIV (HIV Ab), hepatitis B (HBsAg, HBAb) or Hepatitis C (HCV Ab) seropositivity at screening.
15. Any malignancy within the past 5 years, except for basal cell or squamous epithelial carcinomas of the skin or carcinoma in situ of the cervix or anus, that have been resected, with no evidence of metastatic disease for 3 years.
25. Use of concomitant medications, including non-prescription medication, nutritional and herbal supplements within 14 days or 5 and ½ half-lives (whichever is longer) prior to initial dose of study drug, except incidental use of paracetamol.
Additional key exclusion criteria Part B (migraine patients):
28. Greater than an average of 7 migraine days per month in each of the last 3 months prior to screening.
29. Other headache disorders (except for episodic tension-type headache <5 days/month).
30. Greater than or equal to 5 headache days per month of any type/diagnosis (except migraine) in each of the last 3 months prior to screening.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety and tolerability endpoints
Parts A and B, IV administration
• The incidence of treatment-emergent serious adverse events throughout the duration of the study in healthy subjects and migraine patients challenged with a single IV dose of Neublastin compared to placebo
Part A, ID administration
• The incidence of treatment-emergent serious adverse events throughout the duration of the study in healthy subjects challenged with Neublastin or placebo administered ID
Pharmacokinetic endpoints
Parts A and B, IV administration
The PK variable is the concentration of Neublastin in serum at each time point that sample is collected.
Pharmacodynamic endpoints
All parameters will be compared to baseline; baseline is defined as the last value prior to dosing.
Primary Endpoints - Parts A and B
Assessment of pruritus
• The incidence of pruritus in healthy subjects and migraine patients over a 28-day period after challenge with Neublastin or placebo (IV and ID) as measured by items 1 and 2 on the Pruritus Assessment questionnaire
• The severity of pruritus in healthy subjects and migraine patients over a 28-day period after challenge with Neublastin or placebo (IV and ID) as measured by item 3 (Pruritus Average NRS) and item 4 (Peak Pruritus NRS) on the Pruritus Assessment questionnaire
• The duration of pruritus in healthy subjects and migraine patients over a 28-day period after challenge with Neublastin or placebo (IV and ID) as measured by item 1 on the 5-D Pruritus Scale questionnaire
Assessment of rash
• The incidence of rash in healthy subjects and migraine patients over a 28-day period after challenge with Neublastin or placebo (IV and ID) as measured by the Rash Assessment questionnaire
• The area and severity of rash in healthy subjects and migraine patients over a 28-day period after challenge with Neublastin or placebo (IV and ID) as measured by the Eczema Area and Severity Index (EASI)
• The area and severity of rash in healthy subjects and migraine patients over a 28-day period after challenge with Neublastin or placebo (IV and ID) as measured by patient-reported SCORing Atopic Dermatitis (PO SCORAD) score
• Qualitative assessments of rash in healthy subjects and migraine patients over a 28-day period after challenge with Neublastin or placebo (IV and ID) as observed from digital photography of rash
• The incidence and severity of erythema in healthy subjects and migraine patients over a 28 day period after challenge with Neublastin or placebo (IV and ID) as measured by the Erythema index
Primary Endpoints - Part B
Assessment of headache in migraine patients
• The incidence of headache in migraine patients over a 28-day period after challenge with Neublastin or placebo (IV) as measured by the Headache Assessment questionnaire
• The severity (peak measurement) of headache in migraine patients over a 28 day period after challenge with Neublastin or placebo (IV) as measured by the Headache Assessment questionnaire
• The duration of headache in migraine patients over a 28-day period after challenge with Neublastin or placebo (IV) as measured by the Headache Assessment questionnaire
• The incidence of migraine-associated symptoms in migraine patients over a 28-day period after challenge with Neublastin or placebo (IV) as measured by the Headache Assessment questionnaire
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Secondary Endpoints - Parts A and B
Nociceptive thresholds
• The pain detection threshold (PDT) for heat-induced pain in healthy subjects and migraine patients over a 28-day period after challenge with Neublastin or placebo (IV and ID)
• The PDT for cold-induced pain in healthy subjects and migraine patients over a 28-day period after challenge with Neublastin or placebo (IV and ID)
• The PDT for pressure pain in healthy subjects and migraine patients over a 28-day period after challenge with Neublastin or placebo as measured by using a local algometer for the ID group and a pressure cuff for the IV group
• The pain tolerance threshold (PTT) for pressure pain in healthy subjects and migraine patients over a 28-day period after challenge with Neublastin or placebo as measured by using a local algometer for the ID group and a pressure cuff for the IV group
• The area of secondary hyperalgesia in healthy subjects over a 28 day period after challenge with Neublastin or placebo, for ID administration only, as measured by the Von Frey test
Abnormal temperature perception
• The incidence of abnormal temperature perception in healthy subjects and migraine patients over a 28-day period after challenge with Neublastin or placebo (IV and ID) as measured by the Abnormal Temperature Perception Assessment
• The severity of abnormal temperature perception in healthy subjects and migraine patients over a 28-day period after challenge with Neublastin or placebo as measured by the Abnormal Temperature Perception Assessment
• The duration of abnormal temperature perception in healthy subjects and migraine patients over a 28-day period after challenge with Neublastin or placebo as measured by the Abnormal Temperature Perception Assessment
Pharmacokinetics
• The concentration of Neublastin in serum after a single IV dose of Neublastin in healthy subjects and migraine patients at each time point that sample is collected
Safety
• The incidence of treatment-emergent serious adverse events throughout the duration of the study in healthy subjects and migraine patients challenged with a single IV dose of Neublastin compared to placebo
Secondary Endpoints - Parts A
Headache assessment in healthy subjects
• The incidence of headache in healthy subjects over a 28-day period after challenge with Neublastin or placebo (IV and ID) as measured by the Headache Assessment questionnaire
• The severity (peak measurement) of headache in healthy subjects over a 28-day period after challenge with Neublastin or placebo (IV and ID) as measured by the Headache Assessment questionnaire
• The duration of headache in healthy subjects over a 28-day period after challenge with Neublastin or placebo (IV and ID) as measured by the Headache Assessment questionnaire
• The incidence of migraine-associated symptoms in healthy subjects over a 28-day period after challenge with Neublastin or placebo (IV and ID) as measured by the Headache Assessment questionnaire
Safety
• The incidence of treatment-emergent serious adverse events throughout the duration of the study in healthy subjects challenged with Neublastin or placebo administered ID
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
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| 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 | No |
| 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 | Yes |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| 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 | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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