Clinical Trials Register

Summary
EudraCT Number:	2019-003502-28
Sponsor's Protocol Code Number:	AP-325.04
National Competent Authority:	Czechia - SUKL
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2019-12-10
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Czechia - SUKL

A.2

EudraCT number

2019-003502-28

A.3

Full title of the trial

A Randomized, Double-blind, Placebo Controlled, Parallel Group Study to Evaluate the Efficacy and Safety of AP-325 in Subjects with Peripheral Post-surgical Neuropathic Pain

Randomizovaná, dvojitě zaslepená, placebem kontrolovaná studie s paralelními skupinami pro vyhodnocení bezpečnosti a účinnosti AP-325 u subjektů s periferní pooperační neuropatickou bolestí

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Phase 2 study to evaluate the efficacy and safety of a ten-days treament of subjects with peripheral post-surgical neuropathic pain with drug AP-325 or placebo

Studie fáze 2 k vyhodnocení účinnosti a bezpečnosti desetidenní léčby subjektů s periferní pooperační neuropatickou bolestí lékem AP-325 nebo placebem

A.4.1

Sponsor's protocol code number

AP-325.04

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Algiax Pharmaceuticals GmbH
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Algiax Pharmaceuticals GmbH
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Algiax Pharmaceuticals GmbH
B.5.2	Functional name of contact point	Chief Scientific Officer
B.5.3	Address:
B.5.3.1	Street Address	Mettmanner Straße 25, Gebäude 9
B.5.3.2	Town/ city	Erkrath
B.5.3.3	Post code	40699
B.5.3.4	Country	Germany
B.5.4	Telephone number	+492116178510
B.5.6	E-mail	info@algiax.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	AP-325
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	LAFLUNIMUS
D.3.9.1	CAS number	147076-36-6
D.3.9.2	Current sponsor code	AP-325
D.3.9.4	EV Substance Code	SUB08387MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	25
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule, hard
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Peripheral post-surgical neuropathic pain

E.1.1.1

Medical condition in easily understood language

Post-surgical neuropathic pain after breast surgery (cancer interventions), chest surgery (i.e. thoracotomy and sternotomy), groin hernia repair (i.e. femoral hernia repairs, inguinal hernia repairs)

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	LLT
E.1.2	Classification code	10077974
E.1.2	Term	Peripheral neuropathic pain
E.1.2	System Organ Class	100000004852

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To investigate the efficacy of repeat oral dosing of AP-325 on neuropathic pain in subjects with peripheral post-surgical neuropathic pain (PPNP) after 10 days of treatment

E.2.2

Secondary objectives of the trial

- To further investigate the long-lasting efficacy of repeat oral dosing of AP-325 on neuropathic pain over the entire study duration
- To investigate the effect of repeat oral dosing of AP-325 on patient-reported outcomes
- To investigate the effect of repeat oral dosing of AP-325 on the use of rescue medication
- To investigate the effect of repeat oral dosing of AP-325 on the proportion of subjects classified as treatment failure
- To investigate the safety and tolerability of repeat oral dosing of AP-325 in subjects with PPNP
- To evaluate plasma concentrations of AP-325
- To evaluate investigational medicinal product (IMP) concentration-effect relationships
- To evaluate the effect of CYP2C9 polymorphisms on the plasma concentration of AP-325

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Subjects must be at least 18 years and not older than 80 years
2. Subjects with a diagnosis of chronic post-surgical neuropathic pain after breast surgery (breast cancer interventions), chest surgery (i.e. thoracotomy, video assisted thoracoscopy and sternotomy), hernia repair of the abdominal wall (i.e. femoral hernia repairs, inguinal hernia repairs, umbilical hernia repair or incisional hernia repair), abdominal surgery (i.e. cholecystectomy, appendectomy), varicose vein surgery or gynecologic surgery (i.e. hysterectomy, C-section)
3. The chronic post-surgical pain developed or increased in intensity after the surgical procedure and persisted beyond the healing process, i.e. at least 3 months after the initiating event, as defined according to the international association for the study of pain (IASP) classification of chronic pain for ICD-11 (Schug et al., 2019)
4. Subjects must have ‘probable’ or ‘definite’ neuropathic pain as assessed by the revised IASP special interest group on neuropathic pain (NeuPSIG) grading system (Finnerup et al., 2016)
5. Subjects must be willing and able to discontinue and washout prohibited substances including
• pain medications (e.g. antidepressants, anticonvulsants/antiepileptics, selective serotonin and dual reuptake inhibitors, opioids, long-acting benzodiazepines, muscle relaxants, and topical analgesics), except the rescue medication, and
• substances known to be inhibitors or inducers of CYP2C9 and inhibitors of CYP3A4
for specific washout periods of at least 5 times the drug half-life
Note: Subjects using prohibited substances for other indications than neuropathic pain, e.g. antiepileptics for the treatment of epilepsy, may not be included in the study , because a discontinuation of such medication is not medically justifiable.
6. Permitted concomitant medications must have been stable for at least 4 weeks prior to Day -14 and any non-pharmacological therapies (e.g. physiotherapy, acupuncture and transcutaneous electrical neural stimulation) must have been initiated at least 3 weeks prior to Screening
7. Female subjects must not be pregnant or breastfeeding and be
• of non-childbearing potential or
• if of childbearing potential, use a highly effective contraceptive method from start of the IMP intake until 30 days after the last IMP intake and have a negative pregnancy test at Screening (blood test)
8. Male subjects must agree, from start of the IMP intake until 3 months after the last IMP intake, to refrain from donating sperm and use a male condom when having sexual intercourse with a woman of childbearing potential at any time and advise her to use a highly effective contraceptive method
9. Subjects must understand the nature of the study procedures and provide written informed consent prior to any study-related procedures
10. Body weight ≥55 kg for men and ≥50 kg for women
11. Body mass index (BMI) <40 kg/m²

Randomization criteria
1. At least 5 daily pain assessments in the baseline week prior to randomization, with a mean score on the PI-NRS ≥4 and ≤9. Differences between the baseline daily pain scores on the PI-NRS must be ≤50%.
2. For female subjects of childbearing potential: negative pregnancy test in urine on Day 1.

E.4

Principal exclusion criteria

1. Subjects with neuropathic pain not a result of a surgical procedure as defined in inclusion criterion 2
2. Subjects with any other coexisting pain that cannot be discriminated from post-surgical neuropathic pain, in the opinion of the subject or clinician e.g., the pain is at least partially due to pain in deeper structures such as internal organs, joints, muscles or bones
3. Inability to participate in the study, in the opinion of the investigator, because of, for example, severe brain damage, language barrier, dementia, or other clinically significant or unstable conditions
4. Subjects using adjuvant chemotherapy or radiotherapy; adjuvant therapies must have been finished at least weeks prior to the run-in period (Day - 14)
5. Creatinine clearance <60 mL/min using the Cockcroft-Gault formula
6. White blood cell count <2500/mm³; neutrophil count <1500/mm³; platelet count <100 x 10³/mm³
7. Heart rate <50 or >100 beats per minute; systolic blood pressure <100 or >140 mmHg; diastolic blood pressure <50 or >90 mmHg
8. A history of multiple drug allergies
9. History or presence of alcohol or drug abuse
10. Subjects using strong opioids (e.g. a Morphine Equivalent Dose
[MED] >80 mg/day)
11. Positive test for drugs of abuse at Day -7
12. Evidence of depression and/or a score of ≥11 on the HADS depression subscale
13. Psychiatric disease in the past 5 years
14. History of any liver disease within the last 6 months, or migraine, or
kidney dysfunction or disease
15. Clinically significant gastrointestinal conditions, likely interfering
with the study medication, study procedures or the outcome of the study
16. Positive test for human immunodeficiency virus (HIV)
17. Positive test for hepatitis B surface antigen (HBsAg), hepatitis B core
antibody (HBcAb), hepatitis C antibody and/or HIV1/HIV2 antibody at
Screening
18. Participation of subject in an interventional clinical study within 1
month or, if applicable, 5 half-lives of the IMP, whatever is longer,
before Screening or during participation in this study
19. Subjects who were previously enrolled in this clinical study and have taken study medication or terminated due to poor compliance
20. Known hypersensitivity to the active substance or any of the
excipients of the IMP or the rescue medication
21. Subjects dependent (as an employee or relative) on the sponsor or
investigator
22. Subjects committed to an institution by virtue of an order issued
either by the judicial or the administrative authorities
23. Legal incapacity or limited legal capacity

E.5 End points

E.5.1

Primary end point(s)

Change from Baseline to Day 10 in the 5-day average pain intensity score based on the Pain Intensity Numerical Rating Scale (PI-NRS)

E.5.1.1

Timepoint(s) of evaluation of this end point

Baseline to Day 10

E.5.2

Secondary end point(s)

1. Longitudinal analysis of the 5-day average PI-NRS score over time from Baseline until Day 35
2. Changes from Baseline in the 5-day average PI-NRS score (from Baseline to Day 5, 15, 20, 25, 30 and 35)
3. Responder rate: proportion of subjects who have a ≥30% reduction in the 5-day average PI-NRS score relative to Baseline (on Days 5, 10, 15, 25 and 35)
4. Responder rate: proportion of subjects who have a ≥50% reduction in the 5-day average PI-NRS score relative to Baseline (on Days 5, 10, 15, 25 and 35)
5. Proportion of subjects who "much improved" or "very much improved" relative to Baseline on the patient global impression of change (PGIC) on Days 3, 10, 15, and 36
6. Changes from Baseline in the neuropathic pain evaluation using the neuropathic pain symptom inventory (NPSI) questionnaire on Days 3, 10, 15, and 36
7. Changes from Baseline in the 5-day average daily sleep interference scale (DSIS) score (from Baseline to Day 5, 10, 15, 25 and 35)
8. Changes from Baseline in the anxiety and depression assessment using the hospital anxiety and depression scale (HADS) on Days 10 and 36
9. Time to first use of rescue medication after randomization
10. Total amount of rescue medication use (in mg per day) after randomization
11. Proportion of subjects classified as treatment failure and time to classification as treatment failure after randomization
12. Incidence, severity and seriousness of treatment-emergent adverse events (TEAEs)
13. Changes from Baseline in physical examination and vital signs
14. Changes from Baseline in safety laboratory
15. Changes from Baseline in 12-lead electrocardiogram
16. Changes from Baseline in body weight
17. Plasma concentrations of AP-325 at 1 hour post-dose on Days 1 and 10; pre-dose on Days 3 and 10; and on Day 36
18. Accumulation of Ctrough from Day 3 to Day 10
19. Relationship between Ctrough-ss (Day 10) and the change from Baseline to Day 10 in the 5-day average pain intensity score based on the PI-NRS
20. CYP2C9 genotyping

E.5.2.1

Timepoint(s) of evaluation of this end point

1. Baseline to Day 35
2. Baseline to Day 5, 15, 20, 25, 30 and 35
3. Baseline to Day 5, 10, 15, 25 and 35
4. Baseline to Day 5, 10, 15, 25 and 35
5. Days 3, 10, 15, and 36
6. Baseline, Day 3, 10, 15 and 36
7. Baseline to Day 5, 10, 15, 25 and 35
8. Baseline, Day 10 and 36
9. A priori specification not possible, between Day 1 until Day 36
10. A priori specification not possible, between Day 1 until Day 36
11. A priori specification not possible, between Day1 and Day 36
12. A priori specification not possible, between Day1 and Day 36
13. Baseline, Day 1 (only vital signs), 3, 10, 15 and 36
14. Baseline, Day 3, 10, 15 and 36
15. Baseline, Day 3, 10 and 36
16. Baseline, Day 10 and 36
17. Days 1, 3, 10 and 36
18. Day 3 and 10
19. Baseline to Day 10
20. Day 3

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

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

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

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

LVLS

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

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None. After withdrawal patients will receive standard medical care according to individual needs.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2020-01-22

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-02-20

P. End of Trial
P.	End of Trial Status	Ongoing

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